Benzamide derivatives and uses related thereto

ABSTRACT

Benzamide derivatives of formula I are described and have therapeutic utility, particularly in the treatment of diabetes, obesity and related conditions and disorders:

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority of U.S. ProvisionalPatent Application No. 60/811,759, which was filed on Jun. 8, 2006.

BACKGROUND OF THE INVENTION

This invention is generally directed to novel compounds, compositions,and the use of either in methods for modulating hydroxysteroiddehydrogenases, such as 11β-HSD1, and for treating or preventingdiseases associated with the modulation of hydroxysteroiddehydrogenases, such as diabetes and obesity. The methods comprise theadministration, to a patient in need thereof, of a therapeuticallyeffective amount of a benzamide derivative. Novel benzamide derivativesor pharmaceutically acceptable salts, solvates, stereoisomers, orprodrugs thereof are presented herein.

Hydroxysteroid dehydrogenases (HSDs) regulate the occupancy andactivation of steroid hormone receptors by converting steroid hormonesinto their inactive metabolites. For a recent review, see Nobel et al.,Eur. J. Biochem. 2001, 268:4113-4125.

There exist numerous classes of HSDs. The 11-beta-hydroxysteroiddehydrogenases (11β-HSDs) catalyze the interconversion of activeglucocorticoids (such as cortisol and corticosterone), and their inertforms (such as cortisone and 11-dehydrocorticosterone). The isoform11-beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is expressed inliver, adipose tissue, brain, lung and other glucocorticoid tissue andis a potential target for therapy directed at numerous disorders thatmay be ameliorated by reduction of glucocorticoid action, such asdiabetes, obesity and age-related cognitive dysfunction. Seckl, et al.,Endocrinology, 2001, 142:1371-1376.

It is well known that glucocorticoids play a central role in thedevelopment of diabetes and that glucocorticoids enable the effect ofglucagon on the liver. Long et al., J. Exp. Med. 1936, 63: 465-490; andHoussay, Endocrinology 1942, 30: 884-892. In addition, it has been wellsubstantiated that 11β-HSD1 plays an important role in the regulation oflocal glucocorticoid effect and of glucose production in the liver.Jamieson et al., J. Endocrinol. 2000, 165:685-692.

Furthermore, the hypothesized mechanism of action of HSDs in thetreatment of diabetes has been supported by various experimentsconducted in mice and rats. These studies showed that the mRNA levelsand activities of two key enzymes in hepatic glucose production,phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase(G6Pase) were reduced upon administration of HSD inhibitors. Inaddition, blood glucose levels and hepatic glucose production were shownto be reduced in 11β-HSD1 knockout mice. Additional data gathered usingthis murine knockout model also confirm that inhibition of 11β-HSD1 willnot cause hypoglycemia, since the basal levels of PEPCK and G6Pase areregulated independently of glucocorticoids. Kotelevtsev et al., Proc.Natl. Acad. Sci. USA 1997, 94: 14924-14929.

HSDs also play a role in obesity. Obesity is an important factor inSyndrome X as well as type II (non-insulin dependent) diabetes, andomental fat appears to be of central importance in the development ofboth of these disease, as abdominal obesity has been linked with glucoseintolerance, hyperinsulinemia, hypertriglyceridemia, and other factorsof Syndrome X (e.g., raised blood pressure, decreased levels of HDL andincreased levels of VLDL). Montague et al., Diabetes 2000, 49:883-888,2000. It has also been reported that inhibition of the 11β-HSDs inpre-adipocytes (stromal cells) resulted in a decreased rate ofdifferentiation into adipocytes. This is predicted to result indiminished expansion (possibly reduction) of the omental fat depot,which may lead to reduced central obesity. Bujalska et al., Lancet 1997,349:1210-1213.

Inhibition of 11β-HSD1 in mature adipocytes is expected to attenuatesecretion of the plasminogen activator inhibitor 1 (PAI-1), which is anindependent cardiovascular risk factor, as reported in Halleux et al.,J. Clin. Endocrinol. Metab. 1999, 84:4097-4105. In addition, acorrelation has been shown to exist between glucocorticoid activity andcertain cardiovascular risk factors. This suggests that a reduction ofthe glucocorticoid effects would be beneficial in the treatment orprevention of certain cardiovascular diseases. Walker et al.,Hypertension 1998, 31:891-895; and Fraser et al., Hypertension 1999,33:1364-1368.

HSDs have also been implicated in the process of appetite control andtherefore are believed to play an additional role in weight-relateddisorders. It is known that adrenalectomy attenuates the effect offasting to increase both food intake and hypothalamic neuropeptide Yexpression. This suggests that glucocorticoids play a role in promotingfood intake and that inhibition of 11β-HSD1 in the brain may increasesatiety, thus resulting in a decreased food intake. Woods et al.,Science 1998, 280:1378-1383.

Another possible therapeutic effect associated with modulation of HSDsis that which is related to various pancreatic ailments. It is reportedthat inhibition of 11β-HSD1 in murine pancreatic β-cells results inincreased insulin secretion. Davani et al., J. Biol. Chem. 2000,275:34841-34844. This follows from the discovery that glucocorticoidswere previously found to be responsible for reduced pancreatic insulinrelease in vivo, Billaudel et al., Horm. Metab. Res. 1979, 11:555-560.Thus, it is suggested that inhibition of 11β-HSD1 would yield otherbeneficial effects in the treatment of diabetes other than the predictedeffects on the liver and fat reduction.

11β-HSD1 also regulates glucocorticoid activity in the brain and thuscontributes to neurotoxicity. Rajan et al., Neuroscience 1996, 16:65-70;and Seckl et al., Neuroendocrinol. 2000, 18:49-99. Stress and/orglucocorticoids are known to influence cognitive function (de Quervainet al., Nature 1998, 394:787-790), and unpublished results indicatesignificant memory improvement in rats treated with a non-specific11β-HSD inhibitor. These reports, in addition to the known effects ofglucocorticoids in the brain, suggest that inhibiting HSDs in the brainmay have a positive therapeutic effect against anxiety and relatedconditions. Tronche et al., Nature Genetics 1999, 23:99-103. 11β-HSD1reactivates 11-DHC to corticosterone in hippocampal cells and canpotentiate kinase neurotoxicity, resulting in age-related learningimpairments. Therefore, selective inhibitors of 11β-HSD1 are believed toprotect against hippocampal function decline with age. Yau et al., ProcNatl. Acad. Sci. USA 2001, 98:4716-4721. Thus, it has been hypothesizedthat inhibition of 11β-HSD1 in the human brain would protect againstdeleterious glucocorticoid-mediated effects on neuronal function, suchas cognitive impairment, depression, and increased appetite.

HSDs are believed to play a role in immunomodulation based on thegeneral perception that glucocorticoids suppress the immune system.There is known to be a dynamic interaction between the immune system andthe HPA (hypothalamopituitary-adrenal) axis (Rook, Baillier's Clin.Endocrinol. Metab. 2000, 13: 576-581), and glucocorticoids help balancebetween cell-mediated responses and humoral responses. Increasedglucocorticoid activity, which may be induced by stress, is associatedwith a humoral response and as such, the inhibition of 11β-HSD1 mayresult in shifting the response towards a cell-based reaction. Incertain disease states, such as tuberculosis, leprosy, and psoriasis,the immune reaction is typically biased towards a humoral response whena cell-based response might be more appropriate. Inhibition of 11β-HSD1is being studied for use to direct a cell-based response in theseinstances. Mason, Immunology Today 1991, 12:57-60. It follows then, thatan alternative utility of 11β-HSD1 inhibition would be to bolster atemporal immune response in association with immunization to ensure thata cell based response would be obtained.

Recent reports suggest that the levels of glucocorticoid targetreceptors and of HSDs are connected with the risks of developingglaucoma. Stokes et al., Invest. Ophthalmol. 2000, 41:1629-1638.Further, a connection between inhibition of 11β-HSD1 and a lowering ofthe intraocular pressure was reported. Walker et al., poster P3-698 atthe Endocrine society meeting Jun. 12-15, 1999, San Diego. It was shownthat administration of the nonspecific 11β-HSD1 inhibitor,carbenoxolone, resulted in the reduction of the intraocular pressure by20% in normal patients. In the eye, 11β-HSD1 is expressed exclusively inthe basal cells of the corneal epithelium, the non-pigmentedepithelialium of the cornea (the site of aqueous production), ciliarymuscle, and the sphincter and dilator muscles of the iris. In contrast,the distant isoenzyme 11β-hydroxysteroid dehydrogenase type 2(“11β-HSD2”) is highly expressed in the non-pigmented ciliary epitheliumand corneal endothelium. No HSDs have been found at the trabecularmeshwork, which is the site of drainage. Therefore, 11β-HSD1 issuggested to have a role in aqueous production.

Glucocorticoids also play an essential role in skeletal development andfunction but are detrimental to such development and function whenpresent in excess. Glucocorticoid-induced bone loss is partially derivedfrom suppression of osteoblast proliferation and collagen synthesis, asreported in Kim et al., J. Endocrinol. 1999, 162:371 379. It has beenreported that the detrimental effects of glucocorticoids on bone noduleformation can be lessened by administration of carbenoxolone, which is anon-specific 11β-HSD1 inhibitor. Bellows et al., Bone 1998, 23:119-125.Additional reports suggest that 11β-HSD1 may be responsible forproviding increased levels of active glucocorticoid in osteoclasts, andthus in augmenting bone resorption. Cooper et al., Bone 2000,27:375-381. This data suggests that inhibition of 11β-HSD1 may havebeneficial effects against osteoporosis via one or more mechanisms whichmay act in parallel.

It is known that bile acids inhibit 11β-HSD2 and that such inhibitionresults in a shift in the cortisol/cortisone equilibrium in the favor ofcortisol. Quattropani et al., J. Clin. Invest. November 2001,108:1299-305. A reduction in the hepatic activity of 11β-HSD2 istherefore predicted to reverse the cortisol/cortisone equilibrium tofavor cortisone, which could provide therapeutic benefit in diseasessuch as hypertension.

The various isozymes of the 17-beta-hydroxysteroid dehydrogenases(17β-HSDs) bind to androgen receptors or estrogen receptors and catalyzethe interconversion of various sex hormones including estradiol/estroneand testosterone/androstenedione. To date, six isozymes have beenidentified in humans and are expressed in various human tissuesincluding endometrial tissue, breast tissue, colon tissue, and in thetestes. 17-beta-Hydroxysteroid dehydrogenase type 2 (17β-HSD2) isexpressed in human endometrium and its activity has been reported to belinked to cervical cancer. Kitawaki et al., J. Clin. Endocrin. Metab.,2000, 85:1371-3292-3296. 17-beta-Hydroxysteroid dehydrogenase type 3(17β-HSD3) is expressed in the testes and its modulation may be usefulfor the treatment of androgen-related disorders.

Androgens and estrogens are active in their 17β-hydroxy configurations,whereas their 17-keto derivatives do not bind to androgen and estrogenreceptors and are thus inactive. The conversion between the active andinactive forms (estradiol/estrone and testosterone/androstenedione) ofsex hormones is catalyzed by members of the 17β-HSD family. 17β-HSD1catalyzes the formation of estradiol in breast tissue, which isimportant for the growth of malignant breast tumors. Labrie et al., Mol.Cell. Endocrinol. 1991, 78:C113-C118. A similar role has been suggestedfor 17β-HSD4 in colon cancer. English et al., J. Clin. Endocrinol.Metab. 1999, 84:2080-2085. 17β-HSD3 is almost exclusively expressed inthe testes and converts androstenedione into testosterone. Deficiency ofthis enzyme during fetal development leads to malepseudohermaphroditism. Geissler et al., Nat. Genet. 1994, 7:34-39. Both17β-HSD3 and various 3α-HSD isozymes are involved in complex metabolicpathways which lead to androgen shuffles between inactive and activeforms. Penning et al., Biochem. J. 2000, 351:67-77. Thus, modulation ofcertain HSDs can have potentially beneficial effects in the treatment ofandrogen- and estrogen-related disorders.

The 20-alpha-hydroxysteroid dehydrogenases (20α-HSDs) catalyze theinterconversion of progestins (such as between progesterone and20α-hydroxy progesterone). Other substrates for 20α-HSDs include17α-hydroxypregnenolone or 17α-hydroxyprogesterone, leading to 20α-OHsteroids. Several 20α-HSD isoforms have been identified and 20α-HSDs areexpressed in various tissues, including the placenta, ovaries, testesand adrenals. Peltoketo, et al., J. Mol. Endocrinol. 1999, 23:1-11.

The 3-alpha-hydroxysteroid dehydrogenases (3α-HSDs) catalyze theinterconversion of the androgens dihydrotestosterone (DHT) and5α-androstane-3α,17β-diol and the interconversion of the androgens DHEAand androstenedione and therefore play an important role in androgenmetabolism. Ge et al., Biology of Reproduction 1999, 60:855-860.

International Publications Nos. WO 2004/089896 and WO 2004/065351disclose benzamide derivatives and their use as 11β-HSD1 modulators.

Despite the previous research done in the field of HSD inhibition, thereremains a need for novel compounds that are potent inhibitors of thevarious families of HSDs and efficacious for the treatment ofHSD-mediated conditions such as diabetes, obesity, glaucoma,osteoporosis, cognitive disorders, immune disorders, depression,hypertension, and others.

SUMMARY OF THE INVENTION

In brief, the present invention relates to novel compounds, compositionsthereof and methods for modulating the activity of hydroxysteroiddehydrogenases (HSDs), such as 11β-hydroxysteroid dehydrogenases,17β-hydroxysteroid dehydrogenases, 20α-hydroxysteroid dehydrogenases,and 3α-hydroxysteroid dehydrogenases, including all isoforms thereof,including but not limited to 11β-hydroxysteroid dehydrogenase type 1(hereinafter “11β-HSD1”), 11β-hydroxysteroid dehydrogenase type 2(hereinafter “11β-HSD2”), and 17β-hydroxysteroid dehydrogenase type 3(hereinafter “17β-HSD3”). In one embodiment, the compounds of theinvention inhibit HSD activity.

The present invention also relates to methods for treating or preventingdiseases or disorders associated with the action of hydroxysteroiddehydrogenases, comprising administering to a patient in need thereof atherapeutically effective amount of a benzamide derivative or apharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof. The invention encompasses both selective and non-selectiveinhibitors of hydroxysteroid dehydrogenases.

It should be understood that selective and non-selective inhibitors ofhydroxysteroid dehydrogenases each have benefits in the treatment orprevention of diseases associated with, for example, abnormal glucoselevels or hypothalmic function. The invention also encompasses selectiveinhibitors of HSDs. Two types of selectivity are contemplated, that withrespect to selectivity for HSDs as a class over other types of receptorsor gene targets related to glucose metabolism, or those which areselective for various HSDs or specific isoforms thereof compared toother HSDs or specific isoforms thereof.

In one embodiment, the benzamide derivatives can act as selective ornon-selective 11β-HSD inhibitors. The compounds may inhibit theinterconversion of inactive 11-keto steroids with their active hydroxyequivalents. The present invention provides methods by which theconversion of the inactive to the active form may be controlled, and touseful therapeutic effects which may be obtained as a result of suchcontrol. More specifically, but not exclusively, the invention isconcerned with interconversion between cortisone and cortisol in humans.

In another embodiment, the benzamide derivatives of the presentinvention may be orally active.

The benzamide derivatives are also useful for modulation of numerousmetabolic functions including, but not limited to, one or more of: (i)regulation of carbohydrate metabolism, (ii) regulation of proteinmetabolism, (iii) regulation of lipid metabolism, (iv) regulation ofnormal growth and/or development, (v) influence on cognitive function,(vi) resistance to stress and mineralocorticoid activity.

The benzamide derivatives may also be useful for inhibiting hepaticgluconeogenesis, and may also be effective to relieve the effects ofendogenous glucocorticoids in diabetes mellitus, obesity (includingentripetal obesity), neuronal loss and/or the cognitive impairment ofold age. Thus, in a further embodiment, the invention provides the useof an inhibitor of HSDs in methods directed to producing one or moretherapeutic effects in a patient to whom the benzamide derivative isadministered, said therapeutic effects selected from the groupconsisting of inhibition of hepatic gluconeogenesis, an increase ininsulin sensitivity in adipose tissue and muscle, and the prevention ofor reduction in neuronal loss/cognitive impairment due toglucocorticoid-potentiated neurotoxicity or neural dysfunction ordamage.

The invention further provides methods for treating a condition selectedfrom the group consisting of: hepatic insulin resistance, adipose tissueinsulin resistance, muscle insulin resistance, neuronal loss ordysfunction due to glucocorticoid potentiated neurotoxicity, and anycombination of the aforementioned conditions, the methods comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a benzamide derivative.

The benzamide derivatives of the invention are compounds having Formula(I)

or pharmaceutically acceptable salts, solvates, stereoisomers orprodrugs thereof.

R¹ is a member selected from the group consisting of —OH, halogen and(C₁-C₈)haloalkyl.

R² and R³ are members independently selected from the group consistingof halogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy,(C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl and (C₃-C₈)cycloalkyl, wherein nomore than two of R¹, R² and R³ are halogen.

R⁴ is a member selected from the group consisting of hydrogen, halogen,(C₁-C₈)alkyl and (C₃-C₈)cycloalkyl.

R⁵ is selected from the group consisting of (C₁-C₈)alkyl,(C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl, (C₃-C₈)cycloalkyl, and(C₃-C₈)heterocycloalkyl.

For R⁵, any cycloalkyl or heterocycloalkyl portion can be substitutedwith from one to two members selected from the group consisting ofhalogen, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl, (C₂-C₄)hydroxyalkyl, and(C₁-C₄)alkoxy.

X is selected from the group consisting of a bond, (C₁-C₈)alkylene,(C₀-C₈)alkylene-SO₂, and (C₀-C₈)alkylene-C(O).

Y is selected from the group consisting of H, —CN, —N(R′)₂,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl,(C₃-C₈)cycloalkyl, (C₃-C₈)heterocycloalkyl, heteroaryl, and aryl.

For Y, any cycloalkyl portion, heterocycloalkyl portion, aryl portion orheteroaryl portion is optionally substituted with from one to fourmembers selected from the group consisting of halogen, —CN, —NO₂,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy,(C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl, aryl, heteroaryl,(C₃-C₈)cycloalkyl, (C₃-C₈)heterocycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, (C₃-C₈)heterocycloalkyl(C₁-C₆)alkyl,heteroaryl(C₁-C₆)alkyl or aryl(C₁-C₆)alkyl, —C(O)R′, —C(O)OR′,—NR′C(O)OR′, —OR′, —SR′, —OC(O)R′, —C(O)N(R′)₂, —S(O)R′, —SO₂R′,—SO₂N(R′)₂, —N(R′)₂, —NR′C(O)R′, —NR′SO₂R′, -Z-C(O)R′, -Z-CN,-Z-C(O)OR′, -Z-NR′C(O)OR′, -Z-OR′, -Z-OC(O)R′, -Z-C(O)N(R′)₂, -Z-S(O)R′,-Z-SO₂R′, -Z-SO₂N(R′)₂, -Z-N(R′)₂ and -Z-NR′C(O)R′.

R⁶ to R⁹ are members independently selected from hydrogen and(C₁-C₈)alkyl.

Z is a branched or straight chain (C₁-C₈)alkylene group.

Each occurrence of R′ is independently H or an unsubstituted memberselected from the group consisting of (C₁-C₈)alkyl,(C₁-C₄)alkoxy(C₁-C₄)alkyl, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl, or twoR′ groups, when attached to the same nitrogen atom, can be combined withthe nitrogen atom to which they are attached to form a heterocycle orheteroaryl group.

In one embodiment, the invention provides pharmaceutical compositionscomprising a benzamide derivatives and a pharmaceutically acceptablevehicle, carrier, excipient or diluent.

In another embodiment, the invention provides methods for treatinginsulin-dependent diabetes mellitus comprising administering to apatient in need thereof a therapeutically effective amount of abenzamide derivative of Formula (I).

In another embodiment, the invention provides methods for treatingnon-insulin-dependent diabetes mellitus comprising administering to apatient in need thereof a therapeutically effective amount of abenzamide derivative of Formula (I).

In another embodiment, the invention provides methods for treatinginsulin resistance comprising administering to a patient in need thereofa therapeutically effective amount of a benzamide derivative of Formula(I).

In another embodiment, the invention provides methods for treatingobesity comprising administering to a patient in need thereof atherapeutically effective amount of a benzamide derivative of Formula(I).

In another embodiment, the invention provides methods for modulatingcortisol production comprising administering to a patient in needthereof a therapeutically effective amount of a benzamide derivative ofFormula (I).

In another embodiment, the invention provides methods for modulatinghepatic glucose production comprising administering to a patient in needthereof a therapeutically effective amount of a benzamide derivative ofFormula (I).

In another embodiment, the invention provides methods for modulatinghypothalamic function comprising administering to a patient in needthereof a therapeutically effective amount of a benzamide derivative ofFormula (I).

In one embodiment, the invention provides methods for treating ahydroxysteroid dehydrogenase-mediated condition or disorder comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a benzamide derivative of Formula (I).

In a further embodiment, the invention provides methods for modulating ahydroxysteroid dehydrogenase, comprising administering to a patient inneed thereof a therapeutically effective amount of a benzamidederivative of Formula (I).

In still another embodiment, the invention provides methods for treatingan 11β-HSD1-mediated condition or disorder comprising administering to apatient in need thereof a therapeutically effective amount of abenzamide derivative of Formula (I).

In yet another embodiment, the invention provides method for modulatingthe function of 11β-HSD1 in a cell comprising administering to a patientin need thereof a therapeutically effective amount of a benzamidederivative of Formula (I).

In a further embodiment, the invention provides methods for modulating11β-HSD1, comprising administering to a patient in need thereof atherapeutically effective amount of a benzamide derivative of Formula(I).

In one embodiment, the invention provides methods for treating an11β-HSD2-mediated condition or disorder comprising administering to apatient in need thereof a therapeutically effective amount of abenzamide derivative of Formula (I).

In another embodiment, the invention provides method for modulating thefunction of 11β-HSD2 in a cell comprising administering to a patient inneed thereof a therapeutically effective amount of a benzamidederivative of Formula (I).

In a further embodiment, the invention provides methods for modulating11β-HSD2, comprising administering to a patient in need thereof atherapeutically effective amount of a benzamide derivative of Formula(I).

In one embodiment, the invention provides methods for treating an17β-HSD3-mediated condition or disorder comprising administering to apatient in need thereof a therapeutically effective amount of abenzamide derivative of Formula (I).

In another embodiment, the invention provides method for modulating thefunction of 17β-HSD3 in a cell comprising administering to a patient inneed thereof a therapeutically effective amount of a benzamidederivative of Formula (I).

In a further embodiment, the invention provides methods for modulating17β-HSD3, comprising administering to a patient in need thereof atherapeutically effective amount of a benzamide derivative of Formula(I).

These and other embodiments of this invention will be evident uponreference to the following detailed description. To that end, certainpatent and other documents are cited herein to more specifically setforth various embodiments of this invention. Each of these documents arehereby incorporated by reference in their entirety.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the terms have the following meanings:

The term “alkyl” as used herein refers to a straight or branched chain,saturated hydrocarbon having the indicated number of carbon atoms. Forexample, (C₁-C₆)alkyl is meant to include, but is not limited to methyl,ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, hexyl, isohexyl, and neohexyl. An alkyl group canbe unsubstituted or optionally substituted with one or more substituentsas described herein below.

The term “alkenyl” as used herein refers to a straight or branched chainunsaturated hydrocarbon having the indicated number of carbon atoms andat least one double bond. Examples of a (C₂-C₈)alkenyl group include,but are not limited to, ethylene, propylene, 1-butylene, 2-butylene,isobutylene, sec-butylene, 1-pentene, 2-pentene, isopentene, 1-hexene,2-hexene, 3-hexene, isohexene, 1-heptene, 2-heptene, 3-heptene,isoheptene, 1-octene, 2-octene, 3-octene, 4-octene, and isooctene. Analkenyl group can be unsubstituted or optionally substituted with one ormore substituents as described herein below.

The term “alkynyl” as used herein refers to a straight or branched chainunsaturated hydrocarbon having the indicated number of carbon atoms andat least one triple bond. Examples of a (C₂-C₈)alkynyl group include,but are not limited to, acetylene, propyne, 1-butyne, 2-butyne,1-pentyne, 2-pentyne, 1-hexyne, 2-hexyne, 3-hexyne, 1-heptyne,2-heptyne, 3-heptyne, 1-octyne, 2-octyne, 3-octyne and 4-octyne. Analkynyl group can be unsubstituted or optionally substituted with one ormore substituents as described herein below.

The term “alkylene” refers to a divalent alkyl group (e.g., an alkylgroup attached to two other moieties, typically as a linking group).Examples of a (C₁-C₇)alkylene include —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—,—CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂CH₂CH₂—, and—CH₂CH₂CH₂CH₂CH₂CH₂CH₂—, as well as branched versions thereof. Analkylene group can be unsubstituted or optionally substituted with oneor more substituents as described herein below.

The term “alkoxy” as used herein refers to an —O-alkyl group having theindicated number of carbon atoms. For example, a (C₁-C₆)alkoxy groupincludes —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl,—O-sec-butyl, —O-tert-butyl, —O-pentyl, —O-isopentyl, —O-neopentyl,—O-hexyl, —O-isohexyl, and —O-neohexyl.

The term “aminoalkyl,” as used herein, refers to an alkyl group(typically one to six carbon atoms) wherein from one or more of theC₁-C₆ alkyl group's hydrogen atoms is replaced with an amine of formula—N(R^(a))₂, wherein each occurrence of R^(a) is independently —H or(C₁-C₆)alkyl. Examples of aminoalkyl groups include, but are not limitedto, —CH₂NH₂, —CH₂CH₂NH₂—, —CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂CH₂NH₂,—CH₂CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂N(CH₃)₂,t-butylaminomethyl, isopropylaminomethyl and the like.

The term “aryl” as used herein refers to a 6- to 14-membered monocyclic,bicyclic or tricyclic aromatic hydrocarbon ring system. Examples of anaryl group include phenyl and naphthyl. An aryl group can beunsubstituted or optionally substituted with one or more substituents asdescribed herein below.

The term “cycloalkyl” as used herein refers to a 3- to 14-memberedsaturated or unsaturated non-aromatic monocyclic, bicyclic or tricyclichydrocarbon ring system. The bicyclic or tricyclic hydrocarbon ringsystems may be spiro-fused. Included in this class are cycloalkyl groupswhich are fused to a benzene ring. Representative cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl,cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl,1,3-cyclohexadienyl, cycloheptyl, cycloheptenyl, 1,3-cycloheptadienyl,1,4-cycloheptadienyl, -1,3,5-cycloheptatrienyl, cyclooctyl,cyclooctenyl, 1,3-cyclooctadienyl, 1,4-cyclooctadienyl,-1,3,5-cyclooctatrienyl, spiro[5,4]decane, decahydronaphthalene,octahydronaphthalene, hexahydronaphthalene, octahydroindene,hexahydroindene, tetrahydroinden, decahydrobenzocycloheptene,octahydrobenzocycloheptene, hexahydrobenzocycloheptene,tetrahydrobenzocyclopheptene, dodecahydroheptalene, decahydroheptalene,octahydroheptalene, hexahydroheptalene, and tetrahydroheptalene. Acycloalkyl group can be unsubstituted or optionally substituted with oneor more substituents as described herein below.

The term “halo” as used herein refers to —F, —Cl, —Br or —I.

The term “haloalkyl,” as used herein, refers to a C₁-C₆ alkyl groupwherein from one or more of the C₁-C₆ alkyl group's hydrogen atom isreplaced with a halogen atom, which can be the same or different.Examples of haloalkyl groups include, but are not limited to,trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl,pentachloroethyl, and 1,1,1-trifluoro-2-bromo-2-chloroethyl.

The term “heteroaryl” as used herein refers to an aromatic heterocyclering of 5 to 14 members and having at least one heteroatom selected fromnitrogen, oxygen and sulfur, and containing at least 1 carbon atom,including monocyclic, bicyclic, and tricyclic ring systems.Representative heteroaryls are triazolyl, tetrazolyl, oxadiazolyl,pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl,pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl,thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl,phthalazinyl, quinazolinyl, pyrimidyl, azepinyl, oxepinyl, quinoxalinyl.A heteroaryl group can be unsubstituted or optionally substituted withone or more substituents as described herein below.

As used herein, the term “heteroatom” is meant to include oxygen (O),nitrogen (N), and sulfur (S).

As used herein, the term “heterocycle” or “heterocycloalkyl” as usedherein refers to 5- to 14-membered ring systems which are eithersaturated, unsaturated, or aromatic, and which contains from 1 to 4heteroatoms independently selected from nitrogen, oxygen and sulfur, andwherein the nitrogen and sulfur heteroatoms may be optionally oxidized,and the nitrogen heteroatom may be optionally quaternized, includingmonocyclic, bicyclic, and tricyclic ring systems. The bicyclic ortricyclic ring systems may be spiro-fused. The bicyclic and tricyclicring systems may encompass a heterocycle or heteroaryl fused to abenzene ring. The heterocycle may be attached via any heteroatom orcarbon atom. Heterocycles include heteroaryls as defined above.Representative examples of heterocycles include, but are not limited to,aziridinyl, oxiranyl, thiiranyl, triazolyl, tetrazolyl, azirinyl,diaziridinyl, diazirinyl, oxaziridinyl, azetidinyl, azetidinonyl,oxetanyl, thietanyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl,oxazinyl, thiazinyl, diazinyl, dioxanyl, triazinyl, tetrazinyl,imidazolyl, tetrazolyl, pyrrolidinyl, isoxazolyl, furanyl, furazanyl,pyridinyl, oxazolyl, benzoxazolyl, benzisoxazolyl, thiazolyl,benzthiazolyl, thiophenyl, pyrazolyl, triazolyl, pyrimidinyl,benzimidazolyl, isoindolyl, indazolyl, benzodiazolyl, benzotriazolyl,benzoxazolyl, benzisoxazolyl, purinyl, indolyl, isoquinolinyl,quinolinyl and quinazolinyl. A heterocycle group can be unsubstituted oroptionally substituted with one or more substituents as described hereinbelow.

The term “hydroxyalkyl,” as used herein, refers to an alkyl group havingthe indicated number of carbon atoms wherein one or more of the alkylgroup's hydrogen atoms is replaced with an —OH group. Examples ofhydroxyalkyl groups include, but are not limited to, —CH₂OH, —CH₂CH₂OH,—CH₂CH₂CH₂OH, —CH₂CH₂CH₂CH₂OH, —CH₂CH₂CH₂CH₂CH₂OH,—CH₂CH₂CH₂CH₂CH₂CH₂OH, and branched versions thereof.

Substituents for the groups referred to as alkyl, heteroalkyl, alkylene,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl andheterocycloalkenyl can be a variety of groups selected from: —OR′, ═O,═NR′, ═N—OR′, —NR′R″, —SR′, -halo, —SiR′R″R′″, —OC(O)R′, —C(O)R′,—CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′″C(O)NR′R″,—NR′″SO₂NR′R″, —NR″CO₂R′, —NHC(NH₂)═NH, —NR′C(NH₂)═NH, —NHC(NH₂)═NR′,—S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R′, —CN and —NO₂, in a number rangingfrom zero to three, with those groups having zero, one or twosubstituents being exemplary. R′, R″ and R′″ each independently refer tohydrogen, unsubstituted (C₁-C₈)alkyl, unsubstituted hetero(C₁-C₈)alkyl,unsubstituted aryl and aryl substituted with one to three substituentsselected from -halo, unsubstituted alkyl, unsubstituted alkoxy,unsubstituted thioalkoxy and unsubstituted aryl(C₁-C₄)alkyl. When R′ andR″ are attached to the same nitrogen atom, they can be combined with thenitrogen atom to form a 5-, 6- or 7-membered ring. For example, —NR′R″is meant to include 1-pyrrolidinyl and 4-morpholinyl. An alkyl orheteroalkyl group will have from zero to three substituents, with thosegroups having two or fewer substituents being exemplary in the presentinvention. In some embodiments, an alkyl or heteroalkyl radical will beunsubstituted or monosubstituted. An alkyl or heteroalkyl radical can beunsubstituted. From the above discussion of substituents, one of skillin the art will understand that the term “alkyl” is meant to includegroups such as trihaloalkyl (e.g., —CF₃ and —CH₂CF₃).

Exemplary substituents for the alkyl and heteroalkyl radicals areselected from: —OR′, ═O, —NR′R″, —SR′, -halo, —SiR′R″R′″, —OC(O)R′,—C(O)R′, —CO₂R′, —C(O)NR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR″CO₂R′,—NR′″SO₂NR′R″, —S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R′, —CN and —NO₂,where R′, R″ and R′″ are as defined above. Typical substituents areselected from: —OR′, ═O, —NR′R″, -halo, —OC(O)R′, —CO₂R′, —C(O)NR′R″,—OC(O)NR′R″, —NR″C(O)R′, —NR″CO₂R′, —NR′″SO₂NR′R″, —SO₂R′, —SO₂NR′R″,—NR″SO₂R′—CN and —NO₂.

Similarly, substituents for the aryl and heteroaryl groups are variedand selected from: -halo, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN, —NO₂,—CO₂R′, —C(O)NR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′, —NR″CO₂R′,—NR′″C(O)NR′R″, —NR′″SO₂NR′R″, —NHC(NH₂)═NH, —NR′C(NH₂)═NH,—NH—C(NH₂)═NR′, —S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R′, —N₃, —CH(Ph)₂,perfluoroalkoxy and perfluoro(C₁-C₄)alkyl, in a number ranging from zeroto the total number of open valences on the aromatic ring system; andwhere R′, R″ and R′″ are independently selected from hydrogen,unsubstituted (C₁-C₈)alkyl, unsubstituted hetero(C₁-C₈)alkyl,unsubstituted aryl, unsubstituted heteroaryl, unsubstitutedaryl(C₁-C₄)alkyl and unsubstituted aryloxy(C₁-C₄)alkyl. Typically, anaryl or heteroaryl group will have from zero to three substituents, withthose groups having two or fewer substituents being exemplary in thepresent invention. In one embodiment of the invention, an aryl orheteroaryl group will be unsubstituted or monosubstituted. In anotherembodiment, an aryl or heteroaryl group will be unsubstituted.

Exemplary substituents for aryl and heteroaryl groups are selected from:—halo, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN, —NO₂, —CO₂R′, —CONR′R″,—C(O)R′, —OC(O)NR′R″, —NR″C(O)R′, —S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R′,—N₃, —CH(Ph)₂, perfluoroalkoxy and perfluoro(C₁-C₄)alkyl, where R′ andR″ are as defined above. Typically, substituents are selected from:-halo, —OR′, —OC(O)R′, —NR′R″, —R′, —CN, —NO₂, —CO₂R′, —CONR′R″,—NR″C(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R′, perfluoroalkoxy andperfluoro(C₁-C₄)alkyl.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally be replaced with a substituent of the formula-T-C(O)—(CH₂)_(q)—U—, wherein T and U are independently —NH—, —O—, —CH₂—or a single bond, and q is an integer of from 0 to 2. Alternatively, twoof the substituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula-A-(CH₂)_(r)—B—, wherein A and B are independently —CH₂—, —O—, —NH—,—S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or a single bond, and r is an integerof from 1 to 3. One of the single bonds of the new ring so formed mayoptionally be replaced with a double bond. Alternatively, two of thesubstituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula—(CH₂)_(s)—X—(CH₂)_(t)—, where s and t are independently integers offrom 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—.The substituent R′ in —NR′— and —S(O)₂NR′— is selected from hydrogen orunsubstituted (C₁-C₆)alkyl.

It is to be understood that the substituent —CO₂H, as used herein, maybe optionally replaced with bioisosteric replacements such as:

and the like. See, e.g., The Practice of Medicinal Chemistry; Wermuth,C. G., Ed.; Academic Press: New York, 1996; p. 203.

The benzamide derivative can also exist in various isomeric forms,including configurational, geometric and conformational isomers, as wellas existing in various tautomeric forms, particularly those that differin the point of attachment of a hydrogen atom. As used herein, the term“isomer” is intended to encompass all isomeric forms of a benzamidederivative, including tautomeric forms of the compound.

Certain benzamide derivatives may have asymmetric centers and thereforeexist in different enantiomeric and diastereomeric forms. A benzamidederivative can be in the form of an optical isomer or a diastereomer.Accordingly, the invention encompasses benzamide derivatives and theiruses as described herein in the form of their optical isomers,diasteriomers and mixtures thereof, including a racemic mixture. Opticalisomers of the benzamide derivatives can be obtained by known techniquessuch as asymmetric synthesis, chiral chromatography, simulated movingbed technology or via chemical separation of stereoisomers through theemployment of optically active resolving agents.

As used herein and unless otherwise indicated, the term “stereoisomer”or means one stereoisomer of a compound that is substantially free ofother stereoisomers of that compound. For example, a stereomericallypure compound having one chiral center will be substantially free of theopposite enantiomer of the compound. A stereomerically pure compoundhaving two chiral centers will be substantially free of otherdiastereomers of the compound. A typical stereomerically pure compoundcomprises greater than about 80% by weight of one stereoisomer of thecompound and less than about 20% by weight of other stereoisomers of thecompound, for example, greater than about 90% by weight of onestereoisomer of the compound and less than about 10% by weight of theother stereoisomers of the compound, or greater than about 95% by weightof one stereoisomer of the compound and less than about 5% by weight ofthe other stereoisomers of the compound, or greater than about 97% byweight of one stereoisomer of the compound and less than about 3% byweight of the other stereoisomers of the compound.

It should be noted that if there is a discrepancy between a depictedstructure and a name given that structure, the depicted structurecontrols. In addition, if the stereochemistry of a structure or aportion of a structure is not indicated with, for example, bold ordashed lines, the structure or portion of the structure is to beinterpreted as encompassing all stereoisomers of it.

A benzamide derivative can be in the form of a pharmaceuticallyacceptable salt. Depending on its structure, the phrase“pharmaceutically acceptable salt,” as used herein, refers to apharmaceutically acceptable organic or inorganic acid or base salt of abenzamide derivative. Representative pharmaceutically acceptable saltsinclude, e.g., alkali metal salts, alkali earth salts, ammonium salts,water-soluble and water-insoluble salts, such as the acetate, amsonate(4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate,bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium,calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate,dihydrochloride, edetate, edisylate, estolate, esylate, fiunarate,gluceptate, gluconate, glutamate, glycollylarsanilate,hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate,oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate,einbonate), pantothenate, phosphate/diphosphate, picrate,polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate,subacetate, succinate, sulfate, sulfosaliculate, suramate, tannate,tartrate, teoclate, tosylate, triethiodide, and valerate salts.Furthermore, a pharmaceutically acceptable salt can have more than onecharged atom in its structure. In this instance the pharmaceuticallyacceptable salt can have multiple counterions. Hence, a pharmaceuticallyacceptable salt can have one or more charged atoms and/or one or morecounterions.

As used herein, the term “isolated and purified form” means that whenisolated (e.g., from other components of a synthetic organic chemicalreaction mixture), the isolate contains at least 30%, at least 35%, atleast 40%, at least 45%, at least 50%, at least 55%, at least 60%, atleast 65%, at least 70%, at least 75%, at least 80%, at least 85%, atleast 90%, at least 95% or at least 98% of a benzamide derivative byweight of the isolate. In one embodiment, the isolate contains at least95% of a benzamide derivative by weight of the isolate.

As used herein, the term “prodrug” means a derivative of a compound thatcan hydrolyze, oxidize, or otherwise react under biological conditions(in vitro or in vivo) to provide an active compound, particularly abenzamide derivative. Examples of prodrugs include, but are not limitedto, derivatives and metabolites of a benzamide derivative that includebiohydrolyzable groups such as biohydrolyzable amides, biohydrolyzableesters, biohydrolyzable carbamates, biohydrolyzable carbonates,biohydrolyzable ureides, and biohydrolyzable phosphate analogues (e.g.,monophosphate, diphosphate or triphosphate). Prodrugs of compounds withcarboxyl functional groups are the lower alkyl esters of the carboxylicacid. The carboxylate esters are conveniently formed by esterifying anyof the carboxylic acid moieties present on the molecule. Prodrugs cantypically be prepared using well-known methods, such as those describedby Burger's Medicinal Chemistry and Drug Discovery 6^(th) ed. (Donald J.Abraham ed., 2001, Wiley) and Design and Application of Prodrugs (H.Bundgaard ed., 1985, Harwood Academic Publishers Gmfh).

As used herein, the terms “treat”, “treating” and “treatment” refer tothe eradication or amelioration of a disease or symptoms associated witha disease. In certain embodiments, such terms refer to minimizing thespread or worsening of the disease resulting from the administration ofone or more prophylactic or therapeutic agents to a patient with such adisease.

As used herein, the terms “prevent”, “preventing” and “prevention” referto the prevention of the onset, recurrence or spread of the disease in apatient resulting from the administration of a prophylactic ortherapeutic agent.

The term “effective amount” as used herein refers to an amount of abenzamide derivative or other active ingredient sufficient to provide atherapeutic or prophylactic benefit in the treatment or prevention of adisease or to delay or minimize symptoms associated with a disease.Further, a therapeutically effective amount with respect to a benzamidederivative means that amount of therapeutic agent alone, or incombination with other therapies, that provides a therapeutic benefit inthe treatment or prevention of a disease. Used in connection with abenzamide derivative, the term can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of disease, orenhances the therapeutic efficacy of or synergies with anothertherapeutic agent.

As used herein, “syndrome X” refers to a collection of abnormalitiesincluding hyperinsulinemia, obesity, elevated levels of triglycerides,uric acid, fibrinogen, small dense LDL particles and plasminogenactivator inhibitor 1 (PAI-1), and decreased levels of HDL cholesterol.Syndrome X is further meant to include metabolic syndrome.

The terms “modulate”, “modulation” and the like refer to the ability ofa compound to increase or decrease the function, or activity of, forexample, 11β-HSD1. “Modulation”, as used herein in its various forms, isintended to encompass inhibition, antagonism, partial antagonism,activation, agonism and/or partial agonism of the activity associatedwith 11β-HSD1. 11β-HSD1 inhibitors are compounds that, e.g., bind to,partially or totally block stimulation, decrease, prevent, delayactivation, inactivate, desensitize, or down regulate signaltransduction. 11β-HSD1 activators are compounds that, e.g., bind to,stimulate, increase, open, activate, facilitate, enhance activation,sensitize or up regulate signal transduction. The ability of a compoundto modulate 11β-HSD1 can be demonstrated in an enzymatic assay or acell-based assay. For example, the inhibition of 11β-HSD1 may decreasecortisol levels in a patient and/or increase cortisone levels in apatient by blocking the conversion of cortisone to cortisol.Alternatively, the inhibition of 11β-HSD2 can increase cortisol levelsin a patient and/or decrease cortisone levels in a patient by blockingthe conversion of cortisol to cortisone.

A “patient” includes an animal (e.g., cow, horse, sheep, pig, chicken,turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig), in oneembodiment a mammal such as a non-primate and a primate (e.g., monkeyand human), and in another embodiment a human. In one embodiment, apatient is a human. In specific embodiments, the patient is a humaninfant, child, adolescent or adult.

The term “HSD” as used herein, refers to hydroxysteroid dehydrogenaseenzymes in general, including, but not limited to,11-beta-hydroxysteroid dehydrogenases (11β-HSDs), 17-beta-hydroxysteroiddehydrogenases (17β-HSDs), 20-alpha-hydroxysteroid dehydrogenases(20α-HSDs), 3-alpha-hydroxysteroid dehydrogenases (3α-HSDs), and allisoforms thereof.

The term “11β-HSD1” as used herein, refers to the 11-beta-hydroxysteroiddehydrogenase type 1 enzyme, variant, or isoform thereof. 11β-HSD1variants include proteins substantially homologous to native 11β-HSD1,i.e., proteins having one or more naturally or non-naturally occurringamino acid deletions, insertions or substitutions (e.g., 11β-HSD1derivatives, homologs and fragments). The amino acid sequence of a11β-HSD1 variant can be at least about 80% identical to a native11β-HSD1, or at least about 90% identical, or at least about 95%identical.

The term “11β-HSD2” as used herein, refers to the 11-beta-hydroxysteroiddehydrogenase type 2 enzyme, variant, or isoform thereof. 11β-HSD2variants include proteins substantially homologous to native 11β-HSD2,i.e., proteins having one or more naturally or non-naturally occurringamino acid deletions, insertions or substitutions (e.g., 11β-HSD2derivatives, homologs and fragments). The amino acid sequence of a11β-HSD2 variant can be at least about 80% identical to a native11β-HSD2, or at least about 90% identical, or at least about 95%identical. (see Bart et al., J. Med. Chem., 2002, 45:3813-3815).

The term “17β-HSD3” as used herein, refers to the 17-beta-hydroxysteroiddehydrogenase type 3 enzyme, variant, or isoform thereof. 17β-HSD3variants include proteins substantially homologous to native 17β-HSD3,i.e., proteins having one or more naturally or non-naturally occurringamino acid deletions, insertions or substitutions (e.g., 17β-HSD3derivatives, homologs and fragments). The amino acid sequence of a17β-HSD3 variant can be at least about 80% identical to a native17β-HSD3, or at least about 90% identical, or at least about 95%identical.

As used herein, the term “HSD-responsive condition or disorder” andrelated terms and phrases refer to a condition or disorder that respondsfavorably to modulation of a hydroxysteroid dehydrogenase enzyme (HSD).Favorable responses to HSD modulation include alleviation or abrogationof the disease and/or its attendant symptoms, inhibition of the disease,i.e., arrest or reduction of the development of the disease, or itsclinical symptoms, and regression of the disease or its clinicalsymptoms. An HSD-responsive condition or disease may be completely orpartially responsive to HSD modulation. An HSD-responsive condition ordisorder may be associated with inappropriate, e.g., less than orgreater than normal, HSD activity and at least partially responsive toor affected by HSD modulation (e.g., an HSD inhibitor results in someimprovement in patient well-being in at least some patients).Inappropriate HSD functional activity might arise as the result of HSDexpression in cells which normally do not express HSD, decreased HSDexpression or increased HSD expression. An HSD-responsive condition ordisorder may include condition or disorder mediated by any HSD orisoform thereof.

As used herein, the term “11β-HSD1-responsive condition or disorder” andrelated terms and phrases refer to a condition or disorder that respondsfavorably to modulation of 11β-HSD1 activity. Favorable responses to11β-HSD1 modulation include alleviation or abrogation of the diseaseand/or its attendant symptoms, inhibition of the disease, i.e., arrestor reduction of the development of the disease, or its clinicalsymptoms, and regression of the disease or its clinical symptoms. An11β-HSD1-responsive condition or disease may be completely or partiallyresponsive to 11β-HSD1 modulation. An 11β-HSD1-responsive condition ordisorder may be associated with inappropriate, e.g., less than orgreater than normal, 11β-HSD1 activity and at least partially responsiveto or affected by 11β-HSD1 modulation (e.g., a 11β-HSD1 inhibitorresults in some improvement in patient well-being in at least somepatients). Inappropriate 11β-HSD1 functional activity might arise as theresult of 11β-HSD1 expression in cells which normally do not express11β-HSD1, decreased 11β-HSD1 expression or increased 11β-HSD1expression. A 11β-HSD1-responsive condition or disorder may include a11β-HSD1-mediated condition or disorder.

As used herein, the term “11β-HSD2-responsive condition or disorder” andrelated terms and phrases refer to a condition or disorder that respondsfavorably to modulation of 11β-HSD2 activity. Favorable responses to11β-HSD2 modulation include alleviation or abrogation of the diseaseand/or its attendant symptoms, inhibition of the disease, i.e., arrestor reduction of the development of the disease, or its clinicalsymptoms, and regression of the disease or its clinical symptoms. An11β-HSD2-responsive condition or disease may be completely or partiallyresponsive to 11β-HSD2 modulation. An 11β-HSD2-responsive condition ordisorder may be associated with inappropriate, e.g., less than orgreater than normal, 11β-HSD2 activity and at least partially responsiveto or affected by 11β-HSD2 modulation (e.g., a 11β-HSD2 inhibitorresults in some improvement in patient well-being in at least somepatients).

As used herein, the term “17β-HSD3-responsive condition or disorder” andrelated terms and phrases refer to a condition or disorder that respondsfavorably to modulation of 17β-HSD3 activity. Favorable responses to17β-HSD3 modulation include alleviation or abrogation of the diseaseand/or its attendant symptoms, inhibition of the disease, i.e., arrestor reduction of the development of the disease, or its clinicalsymptoms, and regression of the disease or its clinical symptoms. An17β-HSD3-responsive condition or disease may be completely or partiallyresponsive to 17β-HSD3 modulation. An 17β-HSD3-responsive condition ordisorder may be associated with inappropriate, e.g., less than orgreater than normal, 17β-HSD3 activity and at least partially responsiveto or affected by 17β-HSD3 modulation (e.g., a 17β-HSD3 inhibitorresults in some improvement in patient well-being in at least somepatients). Inappropriate 17β-HSD3 functional activity might arise as theresult of 17β-HSD3 expression in cells which normally do not express17β-HSD3, decreased 17β-HSD3 expression or increased 17β-HSD3expression. A 17β-HSD3-responsive condition or disorder may include a17β-HSD3-mediated condition or disorder.

As used herein, the term “HSD-mediated condition or disorder” andrelated terms and phrases refer to a condition or disorder characterizedby inappropriate, e.g., less than or greater than normal, activity of ahydroxysteroid dehydrogenase (HSD). An HSD-mediated condition ordisorder may be completely or partially characterized by inappropriateHSD activity. However, an HSD-mediated condition or disorder is one inwhich modulation of an HSD results in some effect on the underlyingcondition or disease (e.g., an HSD inhibitor results in some improvementin patient well-being in at least some patients).

As used herein, the term “11β-HSD1-mediated condition or disorder” andrelated terms and phrases refer to a condition or disorder characterizedby inappropriate, e.g., less than or greater than normal, 11β-HSD1activity. A 11β-HSD1-mediated condition or disorder may be completely orpartially characterized by inappropriate 11β-HSD1 activity. However, a11β-HSD1-mediated condition or disorder is one in which modulation of11β-HSD1 results in some effect on the underlying condition or disease(e.g., a 11β-HSD1 inhibitor results in some improvement in patientwell-being in at least some patients).

As used herein, the term “11β-HSD2-mediated condition or disorder” andrelated terms and phrases refer to a condition or disorder characterizedby inappropriate, e.g., less than or greater than normal, 11β-HSD2activity. A 11β-HSD2-mediated condition or disorder may be completely orpartially characterized by inappropriate 11β-HSD2 activity. However, a11β-HSD2-mediated condition or disorder is one in which modulation of11β-HSD2 results in some effect on the underlying condition or disease(e.g., a 11β-HSD2 inhibitor results in some improvement in patientwell-being in at least some patients).

As used herein, the term “17β-HSD3-mediated condition or disorder” andrelated terms and phrases refer to a condition or disorder characterizedby inappropriate, e.g., less than or greater than normal, 17β-HSD3activity. A 17β-HSD3-mediated condition or disorder may be completely orpartially characterized by inappropriate 17β-HSD3 activity. However, a17β-HSD3-mediated condition or disorder is one in which modulation of17β-HSD3 results in some effect on the underlying condition or disease(e.g., a 17β-HSD3 inhibitor results in some improvement in patientwell-being in at least some patients).

The following abbreviations are used herein and have the indicateddefinitions: DMEM is Dulbecco's Modified Eagle Medium; Et₃N istriethylamine; EtOAc is ethyl acetate; MeOH is methanol; MS is massspectrometry; NMR is nuclear magnetic resonance; PBS isphosphate-buffered saline; SPA is scintillation proximity assay; THF istetrahydrofuran; and TMS is trimethylsilyl.

Compounds of the Invention

The present invention provides compounds of Formula (I) as well as theirpharmaceutically acceptable salts, solvates, stereoisomers, or prodrugsthereof, or mixtures thereof, collectively referred to as the “thebenzamide derivatives.”

where the variables are as defined above.

In one embodiment, R¹ is —OH, R² is (C₁-C₃)alkyl, R³ is (C₁-C₃)haloalkyland R⁵ is (C₁-C₈)alkyl, in particular, (C₁-C₃)alkyl; (C₁-C₈)haloalkyl,in particular, (C₁-C₄)haloalkyl; or (C₃-C₆)cycloalkyl, in particularcyclopropyl.

In another embodiment, R⁵ is cyclopropyl and R⁶, R⁷, R⁸, and R⁹ arehydrogen.

In still another embodiment, R⁵ is cyclopropyl, X is a bond, and Y iscyclohexyl, which can be substituted with one to four substituents.

In one embodiment, R¹ is —OH, R² is methyl, and R³ is trifluoromethyl.

In one embodiment, the R¹-R³ moiety is:

In another embodiment, the R¹-R³ moiety is:

In one embodiment, alone or in combination with another embodimentdescribed herein, R¹ can be —OH.

In another embodiment, alone or in combination with another embodimentdescribed herein, R² can be (C₁-C₈)alkyl or (C₁-C₃)alkyl.

In another embodiment, alone or in combination with another embodimentdescribed herein, R² can be methyl.

In yet another embodiment, alone or in combination with anotherembodiment described herein, R³ can be (C₁-C₈)haloalkyl or(C₁-C₃)haloalkyl.

In one embodiment, alone or in combination with another embodimentdescribed herein, R³ can be trifluoromethyl.

In one embodiment, alone or in combination with another embodimentdescribed herein, R⁴ can be hydrogen.

In one embodiment, alone or in combination with another embodimentdescribed herein, R⁵ can be (C₃-C₆)cycloalkyl.

In another embodiment, alone or in combination with another embodimentdescribed herein, R⁵ can be cyclopropyl.

In still another embodiment, alone or in combination with anotherembodiment described herein, X is a bond and Y is (C₃-C₈)cycloalkyl.

In yet another embodiment, alone or in combination with anotherembodiment described herein, X is a (C₁-C₈)alkylene.

In still another embodiment, alone or in combination with anotherembodiment described herein, Y is (C₃-C₈)cycloalkyl.

The benzamide derivatives can have asymmetric centers and thereforeexist in different enantiomeric and diastereomeric forms. This inventionrelates to the use of all optical isomers and stereoisomers of thebenzamide derivatives, and mixtures thereof, and to all pharmaceuticalcompositions and methods of treatment that may employ or contain them.

It should be noted that racemates, racemic mixtures, and stereoisomers,particularly diastereomeric mixtures or diastereomerically purecompounds and enantiomers or enantiomerically pure compounds of theabove are all encompassed.

Specific examples of the compounds of Formula (I) are provided below:

The present invention also provides compositions comprising atherapeutically effective amount of a benzamide derivative of Formula(I) and a pharmaceutically acceptable vehicle, carrier, diluent orexcipient.

The invention further provides benzamide derivatives of Formula (I) thatare in isolated and purified form.

The invention provides methods for treating diabetes comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a benzamide derivative of Formula (I).

The invention also provides methods for treating obesity comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a benzamide derivative of Formula (I).

The invention further provides methods for treating an HSD-mediatedcondition or disorder comprising administering to a patient in needthereof a therapeutically effective amount of a benzamide derivative ofFormula (I).

The invention further provides methods for treating an 11β-HSD1-mediatedcondition or disorder comprising administering to a patient in needthereof a therapeutically effective amount of a benzamide derivative ofFormula (I).

The invention further provides methods for treating an 11β-HSD2-mediatedcondition or disorder comprising administering to a patient in needthereof a therapeutically effective amount of a benzamide derivative ofFormula (I).

The invention further provides methods for treating an 17β-HSD3-mediatedcondition or disorder comprising administering to a patient in needthereof a therapeutically effective amount of a benzamide derivative ofFormula (I).

The invention further provides methods for treating an HSD-responsivecondition or disorder comprising administering to a patient in needthereof a therapeutically effective amount of a benzamide derivative ofFormula (I).

The invention further provides methods for treating an11β-HSD1-responsive condition or disorder comprising administering to apatient in need thereof a therapeutically effective amount of abenzamide derivative of Formula (I).

The invention further provides methods for treating an11β-HSD2-responsive condition or disorder comprising administering to apatient in need thereof a therapeutically effective amount of abenzamide derivative of Formula (I).

The invention further provides methods for treating an17β-HSD3-responsive condition or disorder comprising administering to apatient in need thereof a therapeutically effective amount of abenzamide derivative of Formula (I).

Preparation of the Benzamide Derivatives of Formula I

Those skilled in the art will recognize that there are a variety ofmethods available to synthesize molecules represented in the claims. Ingeneral, useful methods for synthesizing compounds represented in theclaims consist of three parts, which may be done in any order: Formationof an amide bond, installation of a —CR¹R²R³ group, and installation ormodification of functional groups appended to the piperidine group andthe —R⁴ containing aryl ring. Retrosynthetic disconnection of thecompounds of the invention into fragments a-d useful for construction ofthe compounds, is shown below:

Several methods for the preparation of claimed compounds are illustrated(eq. 1-3). Equation one demonstrates one method of forming the amidelinkage. In the case of eq. 1 X′ is chosen from an appropriate groupsuch as OH, Cl, and F, or additionally from any group capable ofactivating a carbonyl group for displacement by an amine (i.e. OSu,imidazole, etc.).

The coupling referred to in eq. 1 may be assisted by the use of organicor inorganic bases, activating agents such as HBTU, etc., and also bycatalysts, in particular by those catalysts known in the art whichassist in the formation of amide bonds such as DMAP, HOBT, etc. Examplecoupling partners include carboxylic acid and amine, acyl chloride andamine, acyl fluoride and amine, COOSu and amine and so forth. Thoseskilled in the art will recognize there are other possible combinationswhich will also result in the desired product.

Installation of the —CR¹R²R³ group may occur before or after the centralcoupling reaction, and may be further modified at various times duringthe preparation of the claimed molecules. Equation 2 demonstrates onemethod in which the —CR¹R²R³ group is installed in the form of a ketonebefore the central coupling reaction, followed by further modificationto reach compounds in the claims. Following the central coupling,addition of a nucleophile such as CF₃ ⁻ or CH₃ ⁻ via addition of CF₃TMS,MeLi, MeMgBr or similar reagent completes the installation of the—CR¹R²R³ group. This may be followed by further modification ofsubstituents to complete the preparation.

Alternatively the —CR¹R²R³ group may be installed following the centralcoupling via Friedel-Crafts acylation as in eq. 3. Those skilled in theart will understand that this may or may not be advantageous dependingon the substituent pattern. Further modification as in eqs. 1 and 2 thenprovides the compounds of the claims.

Introduction of the trifluoromethyl carbinol moiety may be achieved viaa variety of methods, some of which are exemplified in eq. 4-6. One mayintroduce the CF₃ group by addition to a ketone via use of CF₃TMS andTBAF, or one may substitute the quaternary ammonium base of TBAF with achiral quaternary base such as in eq. 4 to preferentially produce oneenantiomer in excess (for an example see Caron et al, Synthesis, 2003,1693-1698).

Another useful method is the chiral addition of a nucleophile such asMeLi or MeMgBr mediated via an amine or aminoalcohol additive (eq. 5) toa trifluoromethylketone (for an example see Thompson et al, Tetrahedronlett., 1995, 49, 8937-8940. Yet another useful method is Friedel-Craftsalkylation (eq. 6), which may be done in a fashion to give opticallyactive products via the use of chiral catalysts such as binaphtholderived titanium catalysts (Ishii et al, J. Org. Chem, 2000, 65,1597-1599), and chiral copper catalysts (Zhuang et al, J. Org. Chem,2001, 66, 1009-1013. Asymmetric dihydroxylation of trifluoromethylstyrene can be a highly selective method to synthesize this type ofchiral carbinol. Sharpless dihydroxylation is well established andusually highly enantioselective. As shown the diol is transferred to thecorresponding cyclic sulfate. The sulfate can then be reduced,subsequent hydrolysis gives the desired carbinol (eq. 7). One skilled inthe art will see there are a multitude of methods available for thistransformation. For the most efficient preparation of any particularcompound in the claims, one skilled in the art will recognize that thetiming of the introduction of the —CR¹R²R³ group can vary, and may bethe first, last, or intermediate transformation in the preparation of agiven compound.

A variety of the methods described above have been used to preparecompounds of the invention, some of which are exemplified in theexamples.

Pharmaceutical Compositions

Pharmaceutical compositions and single unit dosage forms comprising abenzamide derivative, or a pharmaceutically acceptable stereoisomer,prodrug, salt, solvate, hydrate, or clathrate thereof, are alsoencompassed by the invention. Individual dosage forms of the inventionmay be suitable for oral, mucosal (including sublingual, buccal, rectal,nasal, or vaginal), parenteral (including subcutaneous, intramuscular,bolus injection, intraarterial, or intravenous), transdermal, or topicaladministration.

Single unit dosage forms of the invention are suitable for oral, mucosal(e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g.,subcutaneous, intravenous, bolus injection, intramuscular, orintraarterial), or transdermal administration to a patient. Examples ofdosage forms include, but are not limited to: tablets; caplets;capsules, such as soft elastic gelatin capsules; cachets; troches;lozenges; dispersions; suppositories; ointments; cataplasms (poultices);pastes; powders; dressings; creams; plasters; solutions; patches;aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage formssuitable for oral or mucosal administration to a patient, includingsuspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions,and elixirs; liquid dosage forms suitable for parenteral administrationto a patient; and sterile solids (e.g., crystalline or amorphous solids)that can be reconstituted to provide liquid dosage forms suitable forparenteral administration to a patient.

The composition, shape, and type of dosage forms of the invention willtypically vary depending on their use. For example, a dosage form usedin the acute treatment of inflammation or a related disease may containlarger amounts of one or more of the active ingredients it comprisesthan a dosage form used in the chronic treatment of the same disease.Similarly, a parenteral dosage form may contain smaller amounts of oneor more of the active ingredients it comprises than an oral dosage formused to treat the same disease or disorder. These and other ways inwhich specific dosage forms encompassed by this invention will vary fromone another will be readily apparent to those skilled in the art. See,e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing,Easton Pa. (1990).

Typical pharmaceutical compositions and dosage forms comprise one ormore carriers, excipients or diluents. Suitable excipients are wellknown to those skilled in the art of pharmacy, and non-limiting examplesof suitable excipients are provided herein. Whether a particularexcipient is suitable for incorporation into a pharmaceuticalcomposition or dosage form depends on a variety of factors well known inthe art including, but not limited to, the way in which the dosage formwill be administered to a patient. For example, oral dosage forms suchas tablets may contain excipients not suited for use in parenteraldosage forms. The suitability of a particular excipient may also dependon the specific active ingredients in the dosage form.

This invention further encompasses anhydrous (e.g., <1% water)pharmaceutical compositions and dosage forms comprising activeingredients, since water can facilitate the degradation of somecompounds. For example, the addition of water (e.g., 5%) is widelyaccepted in the pharmaceutical arts as a means of simulating long-termstorage in order to determine characteristics such as shelf-life or thestability of formulations over time. See, e.g., Jens T. Carstensen, DrugStability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, N.Y.,1995, pp. 379-80. In effect, water and heat accelerate the decompositionof some compounds. Thus, the effect of water on a formulation can be ofgreat significance since moisture and/or humidity are commonlyencountered during manufacture, handling, packaging, storage, shipment,and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. Pharmaceutical compositionsand dosage forms that comprise lactose and at least one activeingredient that comprises a primary or secondary amine can be anhydrousif substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions can be packaged using materials known to prevent exposureto water such that they can be included in suitable formulary kits.Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastics, unit dose containers (e.g., vials),blister packs, and strip packs.

The invention further encompasses pharmaceutical compositions and dosageforms that comprise one or more compounds that reduce the rate by whichan active ingredient will decompose. Such compounds, which are referredto herein as “stabilizers,” include, but are not limited to,antioxidants such as ascorbic acid, pH buffers, or salt buffers.

The benzamide derivatives can be administered to a mammal (human, mouse,rat, rabbit, dog, cat, bovine, pig, monkey etc.) as an 11β-HSD1modulator, a prophylactic or therapeutic drug of diabetes, aprophylactic or therapeutic drug of diabetic complication (retinopathy,nephropathy, neuropathy, cardiac infarction and cerebral infarctionbased on arteriosclerosis etc.), a prophylactic or therapeutic drug ofhyperlipemia, a prophylactic or therapeutic drug of obesity,neurodegenerative disease and the like, or a prophylactic or therapeuticdrug of diseases mediated by 11β-HSD1.

The benzamide derivatives can be administered to a mammal concurrentlywith an additional therapeutic agent for the treatment of a disease,such as diabetes or obesity, with the aim of the prophylaxis ortreatment of a disease. As such, the benzamide derivatives of thepresent invention can be administered in combination with othertherapeutic agents for the treatment or prevention of numerous diseases,including, but not limited to, diabetes and obesity.

Depending on the disease to be treated and the patient's condition, thecompounds of the invention may be administered by oral, parenteral(e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternalinjection or infusion, subcutaneous injection or implant), inhalation,nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal,local) routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. The invention alsocontemplates administration of the compounds of the invention in a depotformulation, in which the active ingredient is released over a definedtime period.

In the case of a combined administration, the benzamide derivatives maybe administered simultaneously with other another therapeutic agent thatis useful for the treatment or prevention of diabetes, obesity or otherdisease or may be administered at a time prior to or subsequent toanother therapeutic agent. In the case of combined administration, apharmaceutical composition containing the benzamide derivative and anadditional therapeutic agent can be administered. Alternatively, apharmaceutical composition containing the benzamide derivative and apharmaceutical composition containing an additional therapeutic agentmay be administered separately. The administration routes of respectivepharmaceutical compositions may be the same or different.

In the case of a combined administration, the benzamide derivatives maybe administered at a dose of 50 mg to 800 mg per administration, whichis given once to several times a day is contemplated (e.g.,once-weekly). In addition, the compound may be administered at a smallerdose. The combined pharmaceutical agent can be administered at a dosegenerally employed for the prophylaxis or treatment of diabetes orobesity or at a smaller dose than that.

Like the amounts and types of excipients, the amounts and specific typesof active ingredients in a dosage form may differ depending on factorssuch as, but not limited to, the route by which it is to be administeredto patients. However, typical dosage forms of the invention comprise abenzamide derivative, or a pharmaceutically acceptable salt, solvate,clathrate, hydrate, polymorph or prodrug thereof. In the treatment orprevention of diabetes, obesity, glaucoma, osteoporosis, cognitivedisorders, immune disorders, depression or other conditions or disordersassociated with the modulation of an hydroxysteroid dehydrogenase, anappropriate dosage level will generally be from about 0.001 to about 100mg per kg patient body weight per day which can be administered insingle or multiple doses. An exemplary dosage level will be from about0.01 to about 25 mg/kg per day or about 0.05 to about 10 mg/kg per day.In other embodiments, a suitable dosage level may be from about 0.01 toabout 25 mg/kg per day, about 0.05 to about 10 mg/kg per day, or about0.1 to about 5 mg/kg per day. Within this range the dosage may be fromabout 0.005 to about 0.05, about 0.05 to about 0.5 or about 0.5 to about5.0 mg/kg per day lie within the range of from about 0.1 mg to about2000 mg per day, given as a single once-a-day dose in the morning buttypically as divided doses throughout the day taken with food. In oneembodiment, the daily dose is administered twice daily in equallydivided doses. A daily dose range can be from about 5 mg to about 500 mgper day, or between about 10 mg and about 300 mg per day. In managingthe patient, the therapy can be initiated at a lower dose, perhaps fromabout 1 mg to about 25 mg, and increased if necessary up to from about200 mg to about 2000 mg per day as either a single dose or divideddoses, depending on the patient's global response.

For multidrug therapy, the weight ratio of the compound of the inventionto the second active ingredient may be varied and will depend upon theeffective dose of each ingredient. Generally, an effective dose of eachwill be used. Thus, for example, when a compound of the invention iscombined with an NSAID, the weight ratio of the compound of theinvention to the NSAID will generally range from about 1000:1 to about1:1000, or about 200:1 to about 1:200. Combinations of a compound of theinvention and other active ingredients will generally also be within theaforementioned range, but in each case, an effective dose of each activeingredient should be used.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

Oral Dosage Forms

Pharmaceutical compositions of the invention that are suitable for oraladministration can be presented as discrete dosage forms, such as, butare not limited to, tablets (e.g., chewable tablets), caplets, capsules,and liquids (e.g., flavored syrups). Such dosage forms containpredetermined amounts of active ingredients, and may be prepared bymethods of pharmacy well known to those skilled in the art. Seegenerally, Remington's Pharmaceutical Sciences, 18th ed., MackPublishing, Easton Pa. (1990).

Typical oral dosage forms of the invention are prepared by combining theactive ingredient(s) in an intimate admixture with at least oneexcipient according to conventional pharmaceutical compoundingtechniques. Excipients can take a wide variety of forms depending on theform of preparation desired for administration. For example, excipientssuitable for use in oral liquid or aerosol dosage forms include, but arenot limited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit forms, in which case solidexcipients are employed. If desired, tablets can be coated by standardaqueous or nonaqueous techniques. Such dosage forms can be prepared byany of the methods of pharmacy. In general, pharmaceutical compositionsand dosage forms are prepared by uniformly and intimately admixing theactive ingredients with liquid carriers, finely divided solid carriers,or both, and then shaping the product into the desired presentation ifnecessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms of theinvention include, but are not limited to, binders, fillers,disintegrants, and lubricants. Binders suitable for use inpharmaceutical compositions and dosage forms include, but are notlimited to, corn starch, potato starch, or other starches, gelatin,natural and synthetic gums such as acacia, sodium alginate, alginicacid, other alginates, powdered tragacanth, guar gum, cellulose and itsderivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropylmethyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystallinecellulose, and mixtures thereof.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.The binder or filler in pharmaceutical compositions of the invention istypically present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

Suitable forms of microcrystalline cellulose include, but are notlimited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICELRC-581, AVICEL-PH-105 (available from FMC Corporation, American ViscoseDivision, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. Anspecific binder is a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or lowmoisture excipients or additives include AVICEL-PH-103™ and Starch 1500LM.

Disintegrants are used in the compositions of the invention to providetablets that disintegrate when exposed to an aqueous environment.Tablets that contain too much disintegrant may disintegrate in storage,while those that contain too little may not disintegrate at a desiredrate or under the desired conditions. Thus, a sufficient amount ofdisintegrant that is neither too much nor too little to detrimentallyalter the release of the active ingredients should be used to form solidoral dosage forms of the invention. The amount of disintegrant usedvaries based upon the type of formulation, and is readily discernible tothose of ordinary skill in the art. Typical pharmaceutical compositionscomprise from about 0.5 to about 15 weight percent of disintegrant,specifically from about 1 to about 5 weight percent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, agar-agar,alginic acid, calcium carbonate, microcrystalline cellulose,croscarmellose sodium, crospovidone, polacrilin potassium, sodium starchglycolate, potato or tapioca starch, pre-gelatinized starch, otherstarches, clays, other algins, other celluloses, gums, and mixturesthereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, andmixtures thereof. Additional lubricants include, for example, a syloidsilica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore,Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co.of Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants are typically used in an amount of less than about 1 weightpercent of the pharmaceutical compositions or dosage forms into whichthey are incorporated.

For oral administration, the compositions can be provided in the form oftablets containing about 1 to about 1000 milligrams of the activeingredient. In other embodiments, the compositions are provided inprovided in the form of tablets containing about 1.0, about 5.0, about10.0, about 15.0, about 20.0, about 25.0, about 50.0, about 75.0, about100.0, about 150.0, about 200.0, about 250.0, about 300.0, about 400.0,about 500.0, about 600.0, about 750.0, about 800.0, about 900.0, orabout 1000.0 milligrams of the active ingredient for the symptomaticadjustment of the dosage to the patient to be treated. The compounds maybe administered on a regimen of 1 to 4 times per day, such as, forexample, once or twice per day.

Delayed Release Dosage Forms

Active ingredients of the invention can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548,5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which isincorporated herein by reference. Such dosage forms can be used toprovide slow or controlled-release of one or more active ingredientsusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled-release formulations known to those of ordinary skill in theart, including those described herein, can be readily selected for usewith the active ingredients of the invention. The invention thusencompasses single unit dosage forms suitable for oral administrationsuch as, but not limited to, tablets, capsules, gelcaps, and capletsthat are adapted for controlled-release.

Controlled-release pharmaceutical products can improve drug therapy overthat achieved by their non-controlled counterparts. Ideally, the use ofan optimally designed controlled-release preparation in medicaltreatment is characterized by a minimum of drug substance being employedto cure or control the condition in a minimum amount of time. Advantagesof controlled-release formulations include extended activity of thedrug, reduced dosage frequency, and increased patient compliance. Inaddition, controlled-release formulations can be used to affect the timeof onset of action or other characteristics, such as blood levels of thedrug, and can thus affect the occurrence of side (e.g., adverse)effects.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled-release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

Parenteral Dosage Forms

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intra-arterial. Becausetheir administration typically bypasses patients' natural defensesagainst contaminants, parenteral dosage forms can be sterile or capableof being sterilized prior to administration to a patient. Examples ofparenteral dosage forms include, but are not limited to, solutions readyfor injection, dry products ready to be dissolved or suspended in apharmaceutically acceptable vehicle for injection, suspensions ready forinjection, and emulsions. For example, lyophilized sterile compositionssuitable for reconstitution into particulate-free dosage forms suitablefor administration to humans.

Suitable vehicles that can be used to provide parenteral dosage forms ofthe invention are well known to those skilled in the art. Examplesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms of the invention.

Parenteral dosage forms are exemplary for the methods of preventing,treating or managing disease in a cancer patient.

Transdermal and Topical Dosage Forms

Transdermal and topical dosage forms of the invention include, but arenot limited to, creams, lotions, ointments, gels, solutions, emulsions,suspensions, or other forms known to one of skill in the art. See, e.g.,Remington's Pharmaceutical Sciences, 18th eds., Mack Publishing, EastonPa. (1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed.,Lea & Febiger, Philadelphia (1985). Transdermal dosage forms include“reservoir type” or “matrix type” patches, which can be applied to theskin and worn for a specific period of time to permit the penetration ofa desired amount of active ingredients.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide transdermal and topical dosage formsencompassed by this invention are well known to those skilled in thepharmaceutical arts, and depend on the particular tissue to which agiven pharmaceutical composition or dosage form will be applied. Withthat fact in mind, typical excipients include, but are not limited to,water, acetone, ethanol, ethylene glycol, propylene glycol,butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil,and mixtures thereof to form lotions, tinctures, creams, emulsions, gelsor ointments, which are non-toxic and pharmaceutically acceptable.Moisturizers or humectants also can be added to pharmaceuticalcompositions and dosage forms if desired. Examples of such additionalingredients are well known in the art. See, e.g., Remington'sPharmaceutical Sciences, 18th eds., Mack Publishing, Easton Pa. (1990).

Depending on the specific tissue to be treated, additional componentsmay be used prior to, in conjunction with, or subsequent to treatmentwith active ingredients of the invention. For example, penetrationenhancers can be used to assist in delivering the active ingredients tothe tissue. Suitable penetration enhancers include, but are not limitedto: acetone; various alcohols such as ethanol, oleyl, andtetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethylacetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such aspolyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; andvarious water-soluble or insoluble sugar esters such as Tween 80(polysorbate 80) and Span 60 (sorbitan monostearate).

The pH of a pharmaceutical composition or dosage form, or of the tissueto which the pharmaceutical composition or dosage form is applied, mayalso be adjusted to improve delivery of one or more active ingredients.Similarly, the polarity of a solvent carrier, its ionic strength, ortonicity can be adjusted to improve delivery. Compounds such asstearates can also be added to pharmaceutical compositions or dosageforms to advantageously alter the hydrophilicity or lipophilicity of oneor more active ingredients so as to improve delivery. In this regard,stearates can serve as a lipid vehicle for the formulation, as anemulsifying agent or surfactant, and as a delivery-enhancing orpenetration-enhancing agent. Different salts, hydrates or solvates ofthe active ingredients can be used to further adjust the properties ofthe resulting composition.

Mucosal Dosage Forms and Lung Delivery

Mucosal dosage forms of the invention include, but are not limited to,ophthalmic solutions, sprays and aerosols, or other forms known to oneof skill in the art. See, e.g., Remington's Pharmaceutical Sciences,18th eds., Mack Publishing, Easton Pa. (1990); and Introduction toPharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia(1985). Dosage forms suitable for treating mucosal tissues within theoral cavity can be formulated as mouthwashes or as oral gels. In oneembodiment, the aerosol comprises a carrier. In another embodiment, theaerosol is carrier free.

A compound of the invention can also be administered directly to thelung by inhalation (see e.g., Tong et al., International Publication No.WO 97/39745; Clark et al, International Publication No. WO 99/47196,which are herein incorporated by reference). For administration byinhalation, a benzamide derivative can be conveniently delivered to thelung by a number of different devices. For example, a Metered DoseInhaler (“MDI”) which utilizes canisters that contain a suitable lowboiling propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas can be used to deliver a benzamide derivativedirectly to the lung. MDI devices are available from a number ofsuppliers such as 3M Corporation, Aventis, Boehringer Ingleheim, ForestLaboratories, Glaxo-Wellcome, Schering Plough and Vectura.

Alternatively, a Dry Powder Inhaler (DPI) device can be used toadminister a benzamide derivative to the lung (See, e.g., Raleigh etal., Proc. Amer. Assoc. Cancer Research Annual Meeting, 1999, 40, 397,which is herein incorporated by reference). DPI devices typically use amechanism such as a burst of gas to create a cloud of dry powder insidea container, which can then be inhaled by the patient. DPI devices arealso well known in the art and can be purchased from a number of vendorswhich include, for example, Fisons, Glaxo-Wellcome, Inhale TherapeuticSystems, ML Laboratories, Qdose and Vectura. A popular variation is themultiple dose DPI (“MDDPI”) system, which allows for the delivery ofmore than one therapeutic dose. MDDPI devices are available fromcompanies such as AstraZeneca, GlaxoWellcome, IVAX, Schering Plough,SkyePharma and Vectura. For example, capsules and cartridges of gelatinfor use in an inhaler or insufflator can be formulated containing apowder mix of the compound and a suitable powder base such as lactose orstarch for these systems.

Another type of device that can be used to deliver a benzamidederivative to the lung is a liquid spray device supplied, for example,by Aradigm Corporation. Liquid spray systems use extremely small nozzleholes to aerosolize liquid drug formulations that can then be directlyinhaled into the lung.

In one embodiment, a nebulizer device is used to deliver a benzamidederivative to the lung. Nebulizers create aerosols from liquid drugformulations by using, for example, ultrasonic energy to form fineparticles that can be readily inhaled (See e.g., Verschoyle et al.,British J Cancer, 1999, 80, Suppl 2, 96, which is herein incorporated byreference). Examples of nebulizers include devices supplied bySheffield/Systemic Pulmonary Delivery Ltd. (See, Armer et al., U.S. Pat.No. 5,954,047; van der Linden et al., U.S. Pat. No. 5,950,619; van derLinden et al., U.S. Pat. No. 5,970,974, which are herein incorporated byreference), Aventis and Batelle Pulmonary Therapeutics. Inhaledcompounds, delivered by nebulizer devices, are currently underinvestigation as treatments for aerodigestive cancer (Engelke et al.,Poster 342 at American Association of Cancer Research, San Francisco,Calif., Apr. 1-5, 2000) and lung cancer (Dahl et al., Poster 524 atAmerican Association of Cancer Research, San Francisco, Calif., Apr.1-5, 2000).

In another embodiment, an electrohydrodynamic (“EHD”) aerosol device isused to deliver a benzamide derivative to the lung. EHD aerosol devicesuse electrical energy to aerosolize liquid drug solutions or suspensions(see e.g., Noakes et al., U.S. Pat. No. 4,765,539; Coffee, U.S. Pat. No.4,962,885; Coffee, International Publication No. WO 94/12285; Coffee,International Publication No. WO 94/14543; Coffee, InternationalPublication No. WO 95/26234, Coffee, International Publication No. WO95/26235, Coffee, International Publication No. WO 95/32807, which areherein incorporated by reference). The electrochemical properties of thecompound of the invention formulation may be important parameters tooptimize when delivering this drug to the lung with an EHD aerosoldevice and such optimization is routinely performed by one of skill inthe art. EHD aerosol devices may more efficiently delivery drugs to thelung than existing pulmonary delivery technologies. Other methods ofintra-pulmonary delivery of a benzamide derivative will be known to theskilled artisan and are within the scope of the invention.

Liquid drug formulations suitable for use with nebulizers and liquidspray devices and EHD aerosol devices will typically include a benzamidederivative with a pharmaceutically acceptable carrier. In someembodiments, the pharmaceutically acceptable carrier is a liquid such asalcohol, water, polyethylene glycol or a perfluorocarbon. Optionally,another material may be added to alter the aerosol properties of thesolution or suspension of a benzamide derivative. This material isliquid such as an alcohol, glycol, polyglycol or a fatty acid. Othermethods of formulating liquid drug solutions or suspension suitable foruse in aerosol devices are known to those of skill in the art (See,e.g., Biesalski, U.S. Pat. No. 5,112,598; Biesalski, U.S. Pat. No.5,556,611, which are herein incorporated by reference). A compound ofthe invention can also be formulated in rectal or vaginal compositionssuch as suppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, a benzamidederivative can also be formulated as a depot preparation. Such longacting formulations can be administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection. Thus,for example, the compounds can be formulated with suitable polymeric orhydrophobic materials (for example, as an emulsion in an acceptable oil)or ion exchange resins, or as sparingly soluble derivatives, forexample, as a sparingly soluble salt.

Other Delivery Systems

Alternatively, other pharmaceutical delivery systems can be employed.Liposomes and emulsions are well known examples of delivery vehiclesthat can be used to deliver a benzamide derivative. Certain organicsolvents such as dimethylsulfoxide can also be employed, althoughusually at the cost of greater toxicity. A compound of the invention canalso be delivered in a controlled release system. In one embodiment, apump can be used (Sefton, CRC Crit. Ref Biomed Eng., 1987, 14, 201;Buchwald et al., Surgery, 1980, 88, 507; Saudek et al., N. Engl. J Med,1989, 321, 574). In another embodiment, polymeric materials can be used(see Medical Applications of Controlled Release, Langer and Wise (eds.),CRC Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability,Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, N.Y.(1984); Ranger and Peppas, J Macromol. Sci. Rev. Macromol. Chem., 1983,23, 61; see also Levy et al., Science 1985, 228, 190; During et al.,Ann. Neurol., 1989,25,351; Howard et al., 1989, J. Neurosurg. 71, 105).In yet another embodiment, a controlled-release system can be placed inproximity of the target of the compounds of the invention, e.g., thelung, thus requiring only a fraction of the systemic dose (see, e.g.,Goodson, in Medical Applications of Controlled Release, supra, vol. 2,pp. 115 (1984)). Other controlled-release system can be used (see e.g.,Langer, Science, 1990, 249, 1527).

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide mucosal dosage forms encompassed by thisinvention are well known to those skilled in the pharmaceutical arts,and depend on the particular site or method which a given pharmaceuticalcomposition or dosage form will be administered. With that fact in mind,typical excipients include, but are not limited to, water, ethanol,ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate,isopropyl palmitate, mineral oil, and mixtures thereof, which arenon-toxic and pharmaceutically acceptable. Examples of such additionalingredients are well known in the art. See, e.g., Remington'sPharmaceutical Sciences, 18th eds., Mack Publishing, Easton Pa. (1990).

The pH of a pharmaceutical composition or dosage form, or of the tissueto which the pharmaceutical composition or dosage form is applied, canalso be adjusted to improve delivery of one or more active ingredients.Similarly, the polarity of a solvent carrier, its ionic strength, ortonicity can be adjusted to improve delivery. Compounds such asstearates can also be added to pharmaceutical compositions or dosageforms to advantageously alter the hydrophilicity or lipophilicity of oneor more active ingredients so as to improve delivery. In this regard,stearates can serve as a lipid vehicle for the formulation, as anemulsifying agent or surfactant, and as a delivery-enhancing orpenetration-enhancing agent. Different salts, hydrates or solvates ofthe active ingredients can be used to further adjust the properties ofthe resulting composition.

Therapeutic Uses of the Benzamide Derivatives

In one embodiment, the invention provides methods of treating orpreventing a condition or disorder associated with the modulation ofhydroxysteroid dehydrogenases by administering to a patient having sucha condition or disorder a therapeutically effective amount of a compoundor composition of the invention. In one group of embodiments, conditionsand disorders, including chronic diseases of humans or other species,can be treated with modulators, stimulators, or inhibitors ofhydroxysteroid dehydrogenases, such as 11β-HSD1.

Treatment or Prevention of Diabetes

Diabetes and diabetic conditions can be treated or prevented byadministration of a therapeutically effective amount of a benzamidederivative.

Types of diabetes that can be treated or prevented by administering atherapeutically effective amount of a benzamide derivative include typeI diabetes mellitus (juvenile onset diabetes, insulin dependent-diabetesmellitus or IDDM), type II diabetes mellitus (non-insulin-dependentdiabetes mellitus or NIDDM), insulinopathies, diabetes associated withpancreatic disorders, diabetes associated with other disorders (such asCushing's Syndrome, acromegaly, pheochromocytoma, glucagonoma, primaryaldosteronism, and somatostatinoma), type A and type B insulinresistance syndromes, lipatrophic diabetes, and diabetes induced byβ-cell toxins.

In some embodiments, the type of diabetes being treated is type IIdiabetes.

Treatment or Prevention of Obesity

Obesity can be treated or prevented by administration of atherapeutically effective amount of a benzamide derivative.

Obesity may have genetic, environmental (e.g., expending less energythan is consumed) and regulatory determinants. Obesity includesexogenous, hyperinsulinar, hyperplasmic, hypothyroid, hypothalamic,symptomatic, infantile, upper body, alimentary, hypogonadal, simple andcentral obesity, hypophyseal adiposity and hyperphagia. Metabolicdisorders, such as hyperlidemia and diabetes, and cardiovasculardisorders, such as hypertension and coronary artery disease, arecommonly associated with obesity.

Complications due to obesity may also be treated or prevented byadministering a therapeutically effective amount of a benzamidederivative. Such complications include, but are not limited to, sleepapnea, Pickwickian syndrome, orthopedic disturbances of weight-bearingand non-weight-bearing joints, and skin disorders resulting fromincreased sweat or skin secretions.

Treatment or Prevention of Other Conditions

Other conditions that can be treated or prevented by administering atherapeutically effective amount of a benzamide derivative include, butare not limited to any condition which is responsive to the modulation,such as inhibition, of hydroxysteroid dehydrogenases or specificisoforms thereof, and thereby benefit from administration of such amodulator. Representative conditions in this regard include, but are notlimited to, metabolic disorders and related cardiovascular risk factorssuch as syndrome X, polycystic ovarian disease, eating disorders (e.g.,anorexia and bulimia), craniopharyngioma, Prader-Willi syndrome,Frohlich's syndrome, hyperlipidemia, dyslipidemia, hypercholesterolemia,hypertriglyceridemia, low HDL levels, high HDL levels, hyperglycemia,insulin resistance, hyperinsulinemia and Cushing's syndrome; diseasesassociated therewith such as hypertension, atherosclerosis, vascularrestenosis, retinopathy and nephropathy; neurologic disorders such asneurodegenerative disease, neuropathy and muscle wasting; cognitivedisorders, such as age-related learning disorders, dementia,neurodegeneration, as well as for improvement of cognitive function insubjects ranging from the severely impaired (e.g., Parkinsons's orAlzheimer's associated dementia) to mildly impaired (e.g.,age-associated memory impairment, drug-induced cognitive impairment) tounimpaired subjects (e.g., cognitive enhancers for the generalpopulation) (see, Sandeep, et al., PNAS, electronically available atwww.pnas.org/cgi/doi/10.1073/pnas.0306996101); androgen and/orestrogen-related disorders such as prostate cancer, colon cancer, breastcancer, benign prostatic hyperplasia, ovarian cancer, uterine cancer,and male pseudohermaphrodism; endometriosis, dementia, depression,psoriasis, glaucoma, osteoporosis, viral infections, inflammatorydisorders, and immune disorders.

Additional Therapeutic Agents

In one embodiment, the present methods for treating or preventingfurther comprise the administration of a therapeutically effectiveamount of another therapeutic agent useful for treating or preventingthe diseases or disorders disclosed herein. In this embodiment, the timein which the therapeutic effect of the other therapeutic agent isexerted overlaps with the time in which the therapeutic effect of thebenzamide derivative is exerted.

The compounds of the invention can be combined or used in combinationwith other agents useful in the treatment, prevention, suppression oramelioration of the conditions or disorders for which compounds of theinvention are useful, including diabetes, obesity, glaucoma,osteoporosis, cognitive disorders, immune disorders, depression andthose pathologies noted above.

Such other agents, or drugs, may be administered, by a route and in anamount commonly used therefore, simultaneously or sequentially with abenzamide derivative. In one embodiment, a pharmaceutical compositioncontains such other drugs in addition to the compound of the inventionwhen a benzamide derivative is used contemporaneously with one or moreother drugs. Accordingly, the pharmaceutical compositions of theinvention include those that also contain one or more other activeingredients or therapeutic agents, in addition to a benzamidederivative.

In one embodiment, for the treatment or prevention of diabetes, abenzamide derivative can be administered with another therapeutic agent,including, but not limited to, anti-diabetic agents such as insulin,inhaled insulin (Exubera®), insulin mimetics, insulin secretogues,sulfonylureas (e.g., glyburide, meglinatide, glimepiride, gliclazide,glipizide, gliquidone, chloropropresponsivemide, tolbutamide,acetohexamide, glycopyramide, carbutamide, glibonuride, glisoxepid,glybuthiazole, glibuzole, glyhexamide, glymidine, glypinamide,phenbutamide, tolcylamide and tolazamide), biguanides (e.g., metformin(Glucophage®)), α-glucosidase inhibitors (e.g., acarbose, voglibose andmiglitol), thiazolidinone compounds (e.g., rosiglitazone (Avandia®),troglitazone (Rezulin®), ciglitazone, pioglitazone (Actos®) andenglitazone), prandial glucose regulators (e.g., repaglinide andnateglinide) and glucagon receptor antagonists.

In another embodiment, for the treatment or prevention of obesity, abenzamide derivative can be administered with another therapeutic agent,including, but not limited to, β3 adrenergic receptor agonists, leptinor derivatives thereof, neuropeptide Y (e.g., NPY5) antagonists, andmazindol.

Examples of other therapeutic agents that may be combined with abenzamide derivative, either administered separately or in the samepharmaceutical compositions, include, but are not limited to: (i)cholesterol lowering agents such as HMG-CoA reductase inhibitors (e.g.,lovastatin, simvastatin (Zocor®), pravastatin, fluvastatin, atorvastatin(Lipitor®) and other statins), bile acid sequestrants (e.g.,cholestyramine and colestipol), vitamin B₃ (also known as nicotinicacid, or niacin), vitamin B₆ (pyridoxine), vitamin B₁₂ (cyanocobalamin),fibric acid derivatives (e.g., gemfibrozil, clofibrate, fenofibrate andbenzafibrate), probucol, nitroglycerin, and inhibitors of cholesterolabsorption (e.g., beta-sitosterol and acylCoA-cholesterolacyltransferase (ACAT) inhibitors such as melinamide), HMG-CoA synthaseinhibitors, squalene epoxidase inhibitors and squalene synthetaseinhibitors; (ii) antithrombotic agents, such as thrombolytic agents(e.g., streptokinase, alteplase, anistreplase and reteplase), heparin,hirudin and warfarin derivatives, β-blockers (e.g., atenolol), βadrenergic agonists (e.g., isoproterenol), angiotensin II antagonists,ACE inhibitors and vasodilators (e.g., sodium nitroprusside, nicardipinehydrochloride, nitroglycerin and enaloprilat); (iii) PPAR agonists,e.g., PPARγ and PPARδ agonists; (iv) DP antagonists; (v) lubricants oremollients such as petrolatum and lanolin, keratolytic agents, vitaminD₃ derivatives (e.g., calcipotriene and calcipotriol (Dovonex®)), PUVA,anthralin (Drithrocreme®), etretinate (Tegison®) and isotretinoin; (vi)glaucoma therapies such as cholinergic agonists (e.g., pilocarpine andcarbachol), cholinesterase inhibitors (e.g., physostigmine, neostigmine,demacarium, echothiophate iodide and isofluorophate), carbonic anhydraseinhibitors (e.g., acetazolamide, dichlorphenamide, methazolamide,ethoxzolamide and dorzolamide), non-selective adrenergic agonists (e.g.,epinephrine and dipivefrin), α₂-selective adrenergic agonists (e.g.,apraclonidine and brimonidine), β-blockers (e.g., timolol, betazolol,levobunolol, carteolol and metipranolol), prostaglandin analogs (e.g.,latanoprost) and osmotic diuretics (e.g., glycerin, mannitol andisosorbide); corticosteroids, such as beclomethasone,methylprednisolone, betamethasone, prednisone, prenisolone,dexamethasone, fluticasone and hydrocortisone, and corticosteroidanalogs such as budesonide; (vii) immunosuppressants such ascyclosporine (cyclosporine A, Sandimmune®, Neoral®), tacrolimus (FK-506,Prograf®), rapamycin (sirolimus, Rapamune®) and other FK-506 typeimmunosuppressants, and mycophenolate, e.g., mycophenolate mofetil(CellCept®); (viii) non-steroidal antiinflammatory agents (NSAIDs) suchas propionic acid derivatives (e.g., alminoprofen, benoxaprofen,bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen,ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin,pirprofen, pranoprofen, suprofen, tiaprofenic acid and tioxaprofen),acetic acid derivatives (e.g., indomethacin, acemetacin, alclofenac,clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac,ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacinand zomepirac), fenamic acid derivatives (e.g., flufenamic acid,meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid),biphenylcarboxylic acid derivatives (e.g., diflunisal and flufenisal),oxicams (e.g., isoxicam, piroxicam, sudoxicam and tenoxican),salicylates (e.g., acetylsalicylic acid and sulfasalazine) and thepyrazolones (e.g., apazone, bezpiperylon, feprazone, mofebutazone,oxyphenbutazone and phenylbutazone); (ix) cyclooxygenase-2 (COX-2)inhibitors such as celecoxib (Celebrex®) and rofecoxib (Vioxx®); (xi)inhibitors of phosphodiesterase type IV (PDE-IV); (xii) opioidanalgesics such as codeine, fentanyl, hydromorphone, levorphanol,meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene,buprenorphine, butorphanol, dezocine, nalbuphine and pentazocine; (xiii)a hepatoprotective agent; and (xiv) other compounds such as5-aminosalicylic acid and prodrugs thereof.

The weight ratio of the compound of the invention to the second activeingredient may be varied and will depend upon the effective dose of eachingredient. Generally, an effective dose of each will be used. Thus, forexample, when a benzamide derivative is combined with an NSAID, theweight ratio of the compound of the invention to the NSAID willgenerally range from about 1000:1 to about 1:1000, such as about 200:1to about 1:200. Combinations of a benzamide derivative and other activeingredients will generally also be within the aforementioned range, butin each case, an effective dose of each active ingredient should beused.

Kits

The invention encompasses kits that can simplify the administration ofthe benzamide derivatives or composition of the invention to a patient.

A typical kit of the invention comprises a unit dosage of a benzamidederivative. In one embodiment, the unit dosage form is in a container,which can be sterile, containing a therapeutically effective amount of abenzamide derivative and a pharmaceutically acceptable vehicle. Inanother embodiment, the unit dosage form is in a container containing atherapeutically effective amount of a benzamide derivative as alyophilate or pharmaceutically acceptable salt. In this instance, thekit can further comprise another container that contains a solutionuseful for the reconstitution of the lyophilate or dissolution of thesalt. The kit can also comprise a label or printed instructions for useof the benzamide derivatives.

In a further embodiment, the kit comprises a unit dosage form of acomposition of the invention.

Kits of the invention can further comprise one or more devices that areuseful for administering the unit dosage forms of the benzamidederivatives or a composition of the invention. Examples of such devicesinclude, but are not limited to, a syringe, a drip bag, a patch or anenema, which optionally contain the unit dosage forms.

The present invention is not to be limited in scope by the specificembodiments disclosed in the examples which are intended asillustrations of a few embodiments of the invention and any embodimentsthat are functionally equivalent are within the scope of this invention.Indeed, various modifications of the invention in addition to thoseshown and described herein will become apparent to those skilled in theart and are intended to fall within the scope of the appended claims. Tothis end, it should be noted that one or more hydrogen atoms or methylgroups may be omitted from the drawn structures consistent with acceptedshorthand notation of such organic compounds, and that one skilled inthe art of organic chemistry would readily appreciate their presence.

EXAMPLES

The benzamide derivatives represented by the formulas of the presentinvention and the methods of making thereof are explained in detail inthe following Examples, which are not to be construed as limiting theinvention.

To a mixture of methyl 4-acetylbenzoate (5.0 g, 28.1 mmol) and CF₃SiMe₃(12.5 mL, 84.2 mmol) in THF (150 mL) TBAF (1.0 M, 78.6 mL, 78.6 mmol)was added dropwise at 0° C. The mixture was then stirred for 2.5 h atroom temperature, diluted with Et₂O (100 mL). The solution was washedwith saturated aqueous NaHCO₃, and brine, dried, and concentrated. Flashchromatography of the residue, using 2:8 EtOAc-hexane, gave methyl4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoate: ¹H NMR (CDCl₃) δ8.07(d, J=8.5 Hz, 2 H), δ 7.67(d, J=8.5 Hz, 2 H), 3.93(s, 3 H), 2.70(br,1H), 1.80(s, 3H); ms 249.1 (M+H⁺).

A mixture of methyl 4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoate(6.0 g, 24.2 mmol) and KOH (2.72 g, 48.4 mmol) in 1,4-dioxane (100 mL)and H₂O (50 mL) was refluxed for 2 h. The reaction mixture was cooled toroom temperature, evaporation of the solvent 1,4-dioxane in vacuo. Theaqueous residue was acidified with 2N HCl and extracted with CH₂Cl₂. Theextracts were washed with brine and dried. Flash chromatography of theresidue, using 3:7 EtOAc-hexane, gave4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoic acid: ¹H NMR (CDCl₃) δ11.0(br, 1H), 7.95(d, J=6.8 Hz, 2 H), 7.71(d, J=6.8 Hz, 2 H), 6.73 (s, 1H), 1.71(s, 3H); ms 235.0 (M+H⁺).

Synthesis of optically active carboxylic acid: a). Methyl4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoate: To a 3 L flaskcontaining methyl 4-acetylbenzoate (60 g, 0.34 mol, 1.0 equiv) in 1.0 LTHF was charged with 96.6 g TMS-CF₃ (0.68 mol, 2.0 equiv) at 0° C. Thesolution was allowed to stir for 30 min. 680 mL tetrabutylammoniumfluoride (1.0M in THF, 0.68 mol, 2.0 equiv) was added dropwise viaaddition funnel over a period of 3 h. After addition, the solution wasallowed to stir for an additional 30 min and warm to room temperature.The solution was concentrated down under reduced pressure. Then themixture was diluted with Sat. NaHCO₃, extracted (4×10% MeOH/CH₂Cl₂). Theorganics were combined, dried (MgSO₄) and concentrated under reducedpressure. Purification by flash chromatography (SiO₂, 15% EtOAc/Hexanes)gave the product as an orange oil.

b). Methyl4-((S)-1,1,1-trifluoro-2-(((S)-1-(naphthalen-1-yl)ethyl)carbamoyloxy)-propan-2-yl)benzoate:To a 500 mL flask containing a portion of product obtained above (25 g,0.1 mol, 1.0 equiv) in 150 mL CH₂Cl₂ was charged with 19.7 g DMAP (0.16mol, 1.6 equiv) at 0° C. 28.5 g 4-nitrophenyl chloroformate (0.14 mol,1.4 equiv) was added in portions. The resulting mixture was allowed tostir for 15 min at 0° C. and 3.0 h at room temperature. The mixture wascooled to 0° C. 34.2 g (S)-1-(1-naphthalenyl)ethanamine (0.2 mol, 2.0equiv) was added in portions. After addition, the solution was allowedto stir at room temperature for 1 h. The mixture was diluted with EtOAc,washed with 6×1 M NaOH, 1 N HCl and brine. The organics was dried andconcentrated under reduced pressure. The two diastereomers were purifiedand separated by flash chromatography (SiO₂, 15% Methyl-t-butylether/Hexanes). The first portion of the two close spots was collectedand concentrated under reduced pressure to give the pure diastereomer ascolorless oil.

c). (S)-4-(1,1,1-Trifluoro-2-hydroxypropan-2-yl)benzoic acid: To a 250mL flask containing product obtained above (13.5 g, 30 mmol, 1.0 equiv)was charged with 70 mL THF, 30 mL H₂O, 30 mL MeOH and 0.73 g LiOH (0.3mol, 10.0 equiv). The resulting mixture was stirred at 45° C. forovernight. The mixture was extracted with CH₂Cl₂. The aqueous layer wasthen acidified with 2 N HCl to pH˜4 and extracted (5×10% MeOH/CH₂Cl₂).The organics were dried (MgSO₄), concentrated under reduced pressure toyield the product as white solid.

Example 1 Preparation of(S)-N-{1-[(1-cyanocyclopropyl)methyl]piperidin-4-yl}-N-cyclopropyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide

a). A solution of 1-Boc-4-piperidone (3.00 g, 15.1 mmol, 1.0 equiv.),cyclopropylamine (1.25 mL, 18.1 mmol, 1.2 equiv.) and AcOH (1.03 mL,18.1 mmol, 1.2 equiv.) in 1,2-dichloroethane (50 mL) was treated at 0°C. with NaBH(OAc)₃ (4.77 g, 22.5 mmol, 1.5 equiv.). After being stirredfor 16 h at 25° C., the reaction was then diluted (EtOAc) and washed(1×1 N aqueous NaOH and 1×brine). The organic layer was dried (Na₂SO₄)and concentrated under reduced pressure to provide the product as a palepink liquid.

b). A solution oftert-butyl-4-(cyclopropylamino)piperidine-1-carboxylate prepared abovein step a (1.50 g, 6.24 mmol, 1.1 equiv.) and(S)-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoic acid (1.33 g, 5.67mmol, 1.0 equiv.) in DMF (28 mL) was treated at 0° C. with EDCI (1.30 g,6.80 mmol, 1.2 equiv.), HOAt (927 mg, 6.80 mmol, 1.2 equiv.) and NaHCO₃(952 mg, 11.3 mmol, 2.0 equiv.) successively. After being stirred at 25°C. for 12 h, the reaction was diluted (EtOAc) and washed (1×10% aqueouscitric acid, 1×saturated aqueous NaHCO₃, and 1×brine). The organic layerwas dried (Na₂SO₄) and concentrated under reduced pressure. Purificationof the residue by flash chromatography (SiO₂, 0-5% MeOH/CH₂Cl₂, gradientelution) gave the product as a white solid.

c). (S)-tert-butyl4-[N-cyclopropyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamido]piperidine-1-carboxylateprepared above in step b (2.33 g, 5.10 mmol, 1.0 equiv.) was treatedwith trifluoroacetic acid (19 mL, 260 mmol, 50 equiv.) at 0° C. Afterbeing stirred at 25° C. for 1 h, the reaction was concentrated underreduced pressure, basified (ice-cold 1 N aqueous NaOH) and extracted(5×10% MeOH/CH₂Cl₂). The combined organic layer was dried (Na₂SO₄) andconcentrated under reduced pressure to provide the product as a paleyellow solid.

d).(S)-N-{1-[(1-cyanocyclopropyl)methyl]piperidin-4-yl}-N-cyclopropyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide.A solution of(S)-N-cyclopropyl-N-(piperidin-4-yl)-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamideprepared above in step c (200 mg, 0.56 mmol, 1.0 equiv.) and1-(iodomethyl)cyclopropanecarbonitrile (140 mg, 0.68 mmol, 1.2 equiv.)in CH₃CN (2.8 mL) was treated with N,N-diisopropylethylamine (118 μL,0.68 mmol, 1.2 equiv.). After being stirred for 17 h at 80° C., thereaction was diluted (EtOAc) and washed (1×saturated aqueous NaHCO₃, and1×brine). The organic layer was dried (Na₂SO₄) and concentrated underreduced pressure. Purification of the residue by flash chromatography(SiO₂, 0-5% MeOH/CH₂Cl₂, gradient elution) gave the title compound as apale yellow solid: ¹H NMR (CDCl₃, 400 MHz) δ 7.58 (d, J=8.2 Hz, 2H),7.48 (d, J=8.4 Hz, 2H), 4.25-4.15 (m, 1H), 3.15-3.11 (m, 2H), 2.58-2.54(m, 2H), 2.45 (s, 2H), 2.18-2.04 (m, 4H), 1.88-1.85 (m, 2H), 1.79 (s,3H), 1.31-1.25 (m, 2H), 0.88-0.85 (m, 2H), 0.62-0.57 (m, 2H), 0.49-0.45(m, 2H); MS(ESI) 436 [M+H]⁺.

Example 2 Preparation of(S)-N-cyclopropyl-N-(1-phenylpiperidin-4-yl)-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide

A solution of(S)-N-cyclopropyl-N-(piperidin-4-yl)-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamideprepared above in step c in Example 1 (43 mg, 0.12 mmol, 1.0 equiv.),bromobenzene (15 μL, 0.14 mmol, 1.2 equiv.), (±)-BINAP (6.7 mg, 0.011mmol, 0.09 equiv.), and t-BuONa (28 mg, 0.29 mmol, 2.4 equiv.) intoluene (150 μL, degassed by Argon for 10 min) was treated withPd₂(dba)₃ (3.3 mg, 0.0036 mmol, 0.03 equiv.) under Argon. After beingstirred for 17 h at 80° C. under argon, the reaction was diluted (EtOAc)and washed (brine). The organic layer was dried (Na₂SO₄) andconcentrated under reduced pressure. Purification of the residue byflash chromatography (SiO₂, 20-50% EtOAc/Hexanes, gradient elution) gavethe title compound as a pale yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ7.59 (d, J=8.3 Hz, 2H), 7.50 (d, J=8.5 Hz, 2H), 7.28-7.25 (m, 2H),6.98-6.96 (m, 2H), 6.88-6.85 (m, 1H), 4.35-4.25 (m, 1H), 3.80-3.75 (m,2H), 2.87-2.82 (m, 2H), 2.62-2.54 (m, 1H), 2.52 (s, 1H), 2.28-2.21 (m,2H), 2.04-2.00 (m, 2H), 1.80 (s, 3H), 0.60-0.57 (m, 2H), 0.49-0.45 (m,2H); MS(ESI) 433 [M+H]⁺.

Example 3 Preparation of(S)-N-[1-(4-cyanophenyl)piperidin-4-yl]-N-cyclopropyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide

Using the methods described above in Example 2, but substituting4-bromobenzonitrile for bromobenzene, the title compound was prepared:¹H NMR (CDCl₃, 500 MHz) δ 7.60 (d, J=8.3 Hz, 2H), 7.49 (d, J=8.9 Hz,2H), 6.89 (d, J=8.9 Hz, 2H), 4.42-4.35 (m, 1H), 3.95-3.90 (m, 2H),3.02-2.95 (m, 2H), 2.62-2.55 (m, 1H), 2.49 (s, 1H), 2.22-2.14 (m, 2H),2.05-2.00 (m, 2H), 1.80 (s, 3H), 0.59-0.54 (m, 2H), 0.45-0.40 (m, 2H);MS(ESI) 458 [M+H]⁺.

Example 4 Preparation of(S)-N-[1-(4-carbomoylphenyl)piperidin-4-yl]-N-cyclopropyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide

A solution of(S)-N-[1-(4-cyanophenyl)piperidin-4-yl]-N-cyclopropyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamideprepared above in Example 3 (29 mg, 0.063 mmol, 1.0 equiv.) in t-BuOH(2.0 mL) was treated with KOH (18 mg, 0.32 mmol, 5.0 equiv.) and stirredfor 17 h at 85° C. The reaction was concentrated under reduced pressureand purification of the residue by flash chromatography (SiO₂, 0-10%MeOH/CH₂Cl₂, gradient elution) gave the title compound as a white solid:¹H NMR (CDCl₃, 500 MHz) 7.73 (d, J=8.1 Hz, 2H), 7.61 (d, J=8.3 Hz, 2H),7.52 (d, J=8.9 Hz, 2H), 6.95 (d, J=8.9 Hz, 2H), 4.44-4.35 (m, 1H),3.97-3.93 (m, 2H), 3.49 (d, J=5.6 Hz, 2H), 3.00-2.94 (m, 2H), 2.58-2.52(m, 1H), 2.45 (s, 1H), 2.20-2.12 (m, 2H), 2.05-2.00 (m, 2H), 1.80 (s,3H), 0.59-0.54 (m, 2H), 0.47-0.42 (m, 2H); MS(ESI) 476 [M+H]⁺.

Example 5 Preparation of(S)-N-cyclopropyl-N-(1-cyclopropylpiperidin-4-yl)-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide

A solution of(S)-N-cyclopropyl-N-(piperidin-4-yl)-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamideprepared above in step c in Example 1 (120 mg, 0.337 mmol, 1.0 equiv.),(1-ethoxycyclopropoxy)trimethylsilane (404 μL, 2.02 mmol, 6.0 equiv.)and AcOH (193 μL, 3.37 mmol, 10 equiv.) in MeOH (2.0 mL) was treatedwith NaBH₃CN (95 mg, 1.52 mmol, 4.5 equiv.). After being stirred for 48h at 25° C. and being refluxed for additional 24 h, the reaction wasdiluted (EtOAc) and washed (1×1 N aqueous NaOH, and 1×brine). Theorganic layer was dried (Na₂SO₄) and concentrated under reducedpressure. Purification of the residue by flash chromatography (SiO₂,0-7% MeOH/CH₂Cl₂, gradient elution) gave the title compound as a paleyellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.55 (d, J=8.2 Hz, 2H), 7.44 (d,J=8.4 Hz, 2H), 4.22-4.13 (m, 1H), 3.12 (d, J=11.5 Hz, 2H), 2.96 (s, br,1H), 2.54-2.50 (m, 1H), 2.39-2.22 (m, 2H), 2.12-1.99 (m, 2H), 1.88-1.82(m, 2H), 1.74 (s, 3H), 1.61-1.57 (m, 1H), 0.88-0.85 (m, 2H), 0.55-0.41(m, 6H); MS(ESI) 398 [M+H]⁺.

Example 6 Preparation of(S)-N-cyclopropyl-N-[1-(cyclopropylmethyl)piperidin-4-yl]-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide

Using the methods described in step d in Example 1, but substituting(bromomethy)cyclopropane for 1-(iodomethyl)cyclopropanecarbonitrile, thetitle compound was prepared: ¹H NMR (CDCl₃, 500 MHz) δ 7.57 (d, J=8.2Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 4.14-4.10 (m, 1H), 3.22-3.18 (m, 2H),2.80 (s, br, 1H), 2.56-2.52 (m, 1H), 2.32-2.28 (m, 2H), 2.17-2.08 (m,4H), 1.92-1.87 (m, 2H), 1.78 (s, 3H), 0.94-0.87 (m, 1H), 0.59-0.51 (m,4H), 0.47-0.42 (m, 2H), 0.14-0.10 (m, 2H); MS(ESI) 411 [M+H]⁺.

Example 7 Preparation of(S)-N-[1-(cyclobutylmethyl)piperidin-4-yl]-N-cyclopropyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide

Using the methods described in step d in Example 1, but substituting(bromomethy)cyclobutane for 1-(iodomethyl)cyclopropanecarbonitrile, thetitle compound was prepared: ¹H NMR (CDCl₃, 500 MHz) δ 7.56 (d, J=8.2Hz, 2H), 7.46 (d, J=8.1 Hz, 2H), 4.15-4.05 (m, 1H), 3.06-2.99 (m, 2H),2.97 (s, br, 1H), 2.60-2.51 (m, 2H), 2.44-2.41 (m, 2H), 2.17-2.04 (m,6H), 1.92-1.40 (m, 6H), 1.71 (s, 3H), 0.58-0.53 (m, 2H), 0.47-0.42 (m,2H); MS(ESI) 425 [M+H]⁺.

Example 8 Preparation of(S)-N-[1-(cyclopentyl)piperidin-4-yl]-N-cyclopropyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide

Using the methods described in step d in Example 1, but substitutingbromocyclopentane for 1-(iodomethyl)cyclopropanecarbonitrile, the titlecompound was prepared: ¹H NMR (CDCl₃, 500 MHz) δ 7.57 (d, J=8.2 Hz, 2H),7.46 (d, J=8.4 Hz, 2H), 4.33-4.23 (m, 1H), 3.14-3.07 (m, 2H), 2.84 (s,br, 1H), 2.55-2.51 (m, 2H), 2.20-2.00 (m, 4H), 1.92-1.86 (m, 4H), 1.78(s, 3H), 1.70-1.40 (m, 6H), 0.58-0.53 (m, 2H), 0.47-0.42 (m, 2H);MS(ESI) 425 [M+H]⁺.

Example 9 Preparation of(S)-N-cyclopropyl-N-[1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl]-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide

A solution of(S)-N-cyclopropyl-N-(piperidin-4-yl)-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamideprepared above in step c in Example 1 (73 mg, 0.20 mmol, 1.0 equiv.),tetrahydro-4H-pyran-4-one (65 μL, 7.0 mmol, 3.5 equiv.) and AcOH (23 μL,0.40 mmol, 2 equiv.) in 1,2-dichloroethane/THF (2/1, 1.5 mL) was treatedwith NaBH(OAc)₃ (210 mg, 1.00 mmol, 5.0 equiv.). After being stirred for48 h at 75° C., the reaction was diluted (EtOAc) and washed (1×1 Naqueous NaOH, and 1×brine). The organic layer was dried (Na₂SO₄) andconcentrated under reduced pressure. Purification of the residue byflash chromatography (SiO₂, 0-10% MeOH/CH₂Cl₂, gradient elution) gavethe title compound as a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.58 (d,J=8.3 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H), 4.26-4.20 (m, 1H), 4.06-4.02 (m,2H), 3.40-3.35 (m, 2H), 3.14-3.07 (m, 2H), 2.55-2.52 (m, 2H), 2.48 (s,br, 1H), 2.39-2.35 (m, 2H), 2.16-2.07 (m, 2H), 1.99-1.93 (m, 2H), 1.79(s, 3H), 1.80-1.73 (m, 2H), 1.65-1.60 (m, 2H), 0.58-0.53 (m, 2H),0.47-0.42 (m, 2H); MS(ESI) 441 [M+H]⁺.

Example 10 Preparation of(S)-N-(1-cyclohexylpiperidin-4-yl)-N-cyclopropyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide

Using the methods described in Example 9, but substituting cyclohexanonefor tetrahydro-4H-pyran-4-one, the title compound was prepared: ¹H NMR(CDCl₃, 500 MHz) δ 7.58 (d, J=8.2 Hz, 2H), 7.47 (d, J=8.5 Hz, 2H),4.30-4.18 (m, 1H), 4.05-3.97 (m, 1H), 3.06-2.97 (m, 2H), 2.62-2.52 (m,1H), 2.55-2.50 (m, 2H), 2.48-2.32 (m, 2H), 2.18-2.05 (m, 2H), 2.00-1.87(m, 3H), 1.86-1.80 (m, 2H), 1.79 (s, 3H), 1.27-1.12 (m, 6H), 0.58-0.53(m, 2H), 0.47-0.42 (m, 2H); MS(ESI) 439 [M+H]⁺.

Example 11 Preparation of(S)-N-[1-(2-cyanoethyl)piperidin-4-yl]-N-cyclopropyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide

A solution of(S)-N-cyclopropyl-N-(piperidin-4-yl)-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamideprepared above in step c in Example 1 (73 mg, 0.20 mmol, 1.0 equiv.) inTHF (0.70 mL) was treated with acrylonitrile (55 μL, 0.84 mmol, 4.2equiv.). After being stirred for 24 h at 50° C., the reaction wasdiluted (EtOAc) and washed (1×1 N aqueous NaOH, and 1×brine). Theorganic layer was dried (Na₂SO₄) and concentrated under reducedpressure. Purification of the residue by flash chromatography (SiO₂,0-10% MeOH/CH₂Cl₂, gradient elution) gave the title compound as acolorless oil: ¹H NMR (CDCl₃, 400 MHz) δ 7.58 (d, J=8.2 Hz, 2H), 7.48(d, J=8.2 Hz, 2H), 4.16-4.09 (m, 1H), 3.02-2.98 (m, 2H), 2.75-2.70 (m,3H), 2.57-2.54 (m, 3H), 2.26-2.20 (m, 2H), 2.15-2.08 (m, 2H), 1.92-1.87(m, 2H), 1.78 (s, 3H), 0.58-0.53 (m, 2H), 0.46-0.42 (m, 2H); MS(ESI) 410[M+H]⁺.

Example 12 Preparation ofN-cyclopropyl-N-{1-[(1r,4r)-4-phenylcyclohexyl]piperidin-4-yl}-4-[(S)-1,1,1-trifluoro-2-hydroxypropan-2-yl]benzamideandN-cyclopropyl-N-{1-[(1s,4s)-4-phenylcyclohexyl]piperidin-4-yl}-4-[(s)-1,1,1-trifluoro-2-hydroxypropan-2-yl]benzamide

A solution of(S)-N-cyclopropyl-N-(piperidin-4-yl)-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamideprepared above in step (c) in Example 1 (73 mg, 0.20 mmol, 1.0 equiv.),4-phenylcyclohezanone (156 mg, 7.00 mmol, 4.5 equiv.) and AcOH (23 μL,0.40 mmol, 2 equiv.) in 1,2-dichloroethane/THF (2/1, 3.0 mL) was treatedwith NaBH(OAc)₃ (211 mg, 1.00 mmol, 5.0 equiv.). After being stirred for72 h at 75° C., the reaction was diluted (EtOAc) and washed (1×1 Naqueous NaOH, and 1×brine). The organic layer was dried (Na₂SO₄) andconcentrated under reduced pressure. Purification of the residue byflash chromatography (SiO₂, 60% EtOAc/Hexanes containing 2.5%triethylamine) gave a as a white solid and b as a white solid.

a: R_(f)=0.40 (60% EtOAc/hexanes containing 2.5% triethylamine); ¹H NMR(CDCl₃, 500 MHz) δ 7.56 (d, J=8.2 Hz, 2H), 7.45 (d, J=8.5 Hz, 2H),7.33-7.27 (m, 4H), 7.19-7.13 (m, 1H), 4.16-4.09 (m, 1H), 3.21-3.15 (m,2H), 2.79-2.69 (m, 1H), 2.58-2.54 (m, 1H), 2.40-2.30 (m, 1H), 2.17-2.00(m, 7H), 1.89-1.82 (m, 4H), 1.77 (s, 3H), 1.68-1.55 (m, 4H), 0.60-0.56(m, 2H), 0.49-0.43 (m, 2H); MS (ESI) 515 [M+H]⁺.

b: R_(f)=0.25 (60% EtOAc/hexanes containing 2.5% triethylamine); ¹H NMR(CDCl₃, 500 MHz) δ 7.59 (d, J=7.7 Hz, 2H), 7.49 (d, J=8.1 Hz, 2H),7.29-7.26 (m, 2H), 7.23-7.16 (m, 3H), 4.26-4.19 (m, 1H), 3.64 (s, 1H),3.10-3.02 (m, 2H), 2.60-2.36 (m, 6H), 2.06-1.83 (m, 7H), 1.80 (s, 3H),1.65-1.55 (m, 4H), 0.62-0.58 (m, 2H), 0.49-0.44 (m, 2H); MS (ESI) 515[M+H]⁺.

Example 13 Preparation ofN-{1-[(1s,4s)-4-cyano-4-phenylcyclohexyl]piperidin-4-yl}-N-cyclopropyl-4-[(S)-1,1,1-trifluoro-2-hydroxypropan-2-yl]benzamideandN-{1-[(1r,4r)-4-cyano-4-phenylcyclohexyl]piperidin-4-yl}-N-cyclopropyl-4-[(S)-1,1,1-trifluoro-2-hydroxypropan-2-yl]benzamide

Using the methods described in Example 13, but substituting4-cyano-4-phenylcyclohexanone for 4-phenylcyclohexanone, the titlecompounds were prepared.

a: ¹H NMR (CDCl₃, 500 MHz) δ 7.58 (d, J=8.2 Hz, 2H), 7.55-7.50 (m, 2H),7.47 (d, J=8.4 Hz, 2H), 7.42-7.36 (m, 2H), 7.33-7.28 (m, 1H), 4.16-4.09(m, 1H), 3.60 (s, 1H), 3.15-3.07 (m, 2H), 2.70-2.60 (m, 1H), 2.63-2.58(m, 1H), 2.43-2.33 (m, 3H), 2.10-1.83 (m, 11H), 1.78 (s, 3H), 0.60-0.56(m, 2H), 0.49-0.43 (m, 2H); MS (ESI) 540 [M+H]⁺.

b: ¹H NMR (CDCl₃, 500 MHz) δ 7.63 (d, J=9.1 Hz, 2H), 7.51-7.47 (m, 2H),7.49 (d, J=8.2 Hz, 2H), 7.42-7.36 (m, 2H), 7.34-7.30 (m, 1H), 4.23-4.15(m, 1H), 3.10-3.02 (m, 2H), 2.70-2.40 (m, 5H), 2.30-2.25 (m, 2H),2.13-1.83 (m, 10H), 1.76 (s, 3H), 0.61-0.58 (m, 2H), 0.49-0.45 (m, 2H);MS (ESI) 540 [M+H]⁺.

Example 14 Preparation of(S)-N-(1-benzylpiperidin-4-yl)-N-cyclopropyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide

Using the methods described in step (d) in Example 1, but substitutingbenzyl bromide for 1-(iodomethyl)cyclopropanecarbonitrile, the titlecompound was prepared: ¹H NMR (CDCl₃, 400 MHz) δ 7.58 (d, J=8.1 Hz, 2H),7.47 (d, J=8.2 Hz, 2H), 7.35-7.27 (m, 5H), 4.22-4.16 (m, 1H), 3.58-3.49(m, 2H), 3.00-2.96 (m, 2H), 2.56-2.48 (m, 2H), 2.20-2.08 (m, 4H),1.91-1.80 (m, 2H), 1.79 (s, 3H), 0.59-0.56 (m, 2H), 0.48-0.42 (m, 2H);MS(ESI) 447 [M+H]⁺.

Example 15 Preparation of(S)-N-{1-[(1-carbamoylcyclopropyl)methyl]piperidin-4-yl}-N-cyclopropyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide

Using the methods described in Example 4, but substituting(S)-N-{1-[(1-cyanocyclopropyl)methyl]piperidin-4-yl}-N-cyclopropyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamidefor(S)-N-[1-(4-cyanophenyl)piperidin-4-yl]-N-cyclopropyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamidethe title compound was prepared: ¹H NMR (CDCl₃, 400 MHz) δ 9.15 (s, 1H),7.59 (d, J=8.2 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H), 5.38 (s, 1H), 4.12-4.08(m, 1H), 3.24-3.19 (m, 2H), 2.68 (s, 1H), 2.61-2.57 (m, 1H), 2.48 (s,2H), 2.18-2.04 (m, 4H), 1.94-1.89 (m, 2H), 1.79 (s, 3H), 1.32-1.27 (m,2H), 0.62-0.49 (m, 4H), 0.45-0.42 (m, 2H); MS(ESI) 454 [M+H]⁺.

Example 16 Preparation of a mixture ofN-[(3R,4R)-1-benzyl-3-methylpiperidin-4-yl]-N-cyclopropyl-4-[(S)-1,1,1-trifluoro-2-hydroxypropan-2-yl]benzamideandN-[(3S,4S)-1-benzyl-3-methylpiperidin-4-yl]-N-cyclopropyl-4-[(S)-1,1,1-trifluoro-2-hydroxypropan-2-yl]benzamideand a mixture ofN-[(3S,4R)-1-benzyl-3-methylpiperidin-4-yl)-N-cyclopropyl-4-[(s)-1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamideandN-[(3R,4S)-1-benzyl-3-methylpiperidin-4-yl)-N-cyclopropyl-4-[(S)-1,1,1-trifluoro-2-hydroxypropan-2-yl]benzamide

a). A solution of 1-benzyl-3-methyl-4-piperidone (1.01 g, 4.92 mmol, 1.0equiv.), cyclopropylamine (1.02 mL, 14.8 mmol, 3.0 equiv.) and AcOH(0.84 mL, 14.8 mmol, 3.0 equiv.) in 1,2-dichloroethane (24 mL) wastreated at 0° C. with NaBH(OAc)₃ (3.13 g, 14.8 mmol, 3.0 equiv.). Afterbeing stirred for 16 h at 25° C., the reaction was then diluted (EtOAc)and washed (1×1 N aqueous NaOH and 1×brine). The organic layer was dried(Na₂SO₄) and concentrated under reduced pressure to provide the productas a yellow liquid.

b). A solution of 1-benzyl-N-cyclopropyl-3-methylpiperidin-4-amineprepared above in step a (312 mg, 1.28 mmol, 1.0 equiv.) and(S)-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoic acid (300 mg, 1.28mmol, 1.0 equiv.) in DMF (3.0 mL) was treated at 0° C. with EDCI (320mg, 1.66 mmol, 1.3 equiv.), HOAt (226 mg, 1.66 mmol, 1.3 equiv.) andNaHCO₃ (215 mg, 2.56 mmol, 2.0 equiv.) successively. After being stirredat 25° C. for 3 days, 3-dimethylamino-1-propylamine (322 μL, 2.56 mmol,2.0 equiv.) was added and the reaction was stirred at 25° C. foradditionally 10 min. The reaction was then diluted (EtOAc) and washed(1×10% aqueous citric acid, 1×saturated NaHCO₃, and 1×brine). Theorganic layer was dried (Na₂SO₄) and concentrated under reducedpressure. Purification of the residue by flash chromatography (SiO₂,0-5% MeOH/CH₂Cl₂, gradient elution) gave a as a white solid and b as awhite solid.

a: R_(f)=0.30 (10% MeOH/CH₂Cl₂); ¹H NMR (CDCl₃, 400 MHz) δ 7.58 (d,J=8.1 Hz, 2H), 7.49 (d, J=8.3 Hz, 2H), 7.33-7.28 (m, 5H), 4.41-4.34 (m,1H), 3.54-3.40 (m, 2H), 3.03-2.98 (m, 1H), 2.71-2.66 (m, 1H), 2.62-2.57(m, 1H), 2.56-2.47 (m, 1H), 2.45-2.40 (m, 1H), 2.37-2.32 (m, 1H),2.27-2.23 (m, 1H), 2.10-2.04 (m, 1H), 1.89-1.82 (m, 1H), 1.79 (s, 3H),1.21 (d, J=6.9 Hz, 3H), 0.70-0.66 (m, 1H), 0.52-0.46 (m, 2H), 0.35-0.29(m, 1H); MS (ESI) 461 [M+H]⁺.

b: R_(f)=0.25 (10% MeOH/CH₂Cl₂); ¹H NMR (CDCl₃, 400 MHz) δ 7.63 (d,J=8.3 Hz, 2H), δ 7.57 (d, J=8.2 Hz, 2H), 7.36-7.28 (m, 5H), 4.05-3.70(s, br, 1H), 3.54-3.47 (m, 2H), 2.98-2.90 (m, 2H), 2.70-2.05 (m, 5H),1.82-1.68 (m, 2H), 1.79 (s, 3H), 0.93 (d, J=6.9 Hz, 3H), 0.58-0.38 (m,4H); MS (ESI) 461 [M+H]⁺.

Example 17 Preparation of(S)-N-[1-(2-cyano-2-methylpropyl)piperidin-4-yl]-N-cyclopropyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide

a). To a solution of cyano-dimethyl-acetic acid ethyl ester (7.00 g,49.6 mmol, 1.0 equiv.) which was prepared as described in the reference(P. M. O'Brien et al., J. Med. Chem. 1996, 39, 2354-2366) in1,2-dimethoxyethane/MeOH (10/1, 100 mL) was added NaBH₄ (3.77 g, 99.2mmol, 2.0 equiv.) slowly at 0° C. After being stirred for 16 h at 25°C., the reaction was quenched (saturated aqueous NH₄Cl) cautiously andthe resulting solution was stirred at 25° C. for additional 1 h. Thereaction mixture was then diluted (EtOAc) and washed (1×H₂O and1×brine). The organic layer was dried (Na₂SO₄) and concentrated underreduced pressure to provide the product as a colorless liquid.

b). A solution of 3-hydroxy-2,2-dimethylpropanenitrile prepared above instep a (300 mg, 3.02 mmol, 1.1 equiv.) in pyridine (6.0 mL) was treatedat 0° C. with TsCl (576 mg, 3.02 mmol, 1.0 equiv.). After being stirredat 25° C. for 12 h, the reaction was diluted (EtOAc) and washed(3×ice-cold 1 N aqueous HCl, 1×saturated aqueous NaHCO₃, and 1×brine).The organic layer was dried (Na₂SO₄) and concentrated under reducedpressure. Purification of the residue by flash chromatography (SiO₂,10-20% EtOAc/hexanes, gradient elution) gave the product as a whitesolid.

c). A mixture of toluene-4-sulfonic acid 2-cyano-2,2-dimethy-ethyl esterprepared above in step b (200 mg, 0.79 mmol, 1.0 equiv.) and1,4-dioxa-8-azaspiro[4,5]decane (237 mg, 1.66 mmol, 2.1 equiv.) wasplaced in a sealed tube. After being stirred at 125° C. for 12 h, thereaction was diluted (EtOAc) and washed (1×1 N aqueous NaOH and1×brine). The organic layer was dried (Na₂SO₄) and concentrated underreduced pressure. Purification of the residue by flash chromatography(SiO₂, 0-5% MeOH/CH₂Cl₂, gradient elution) gave the product as a yellowfilm.

d). 3-(1,4-Dioxa-8-aza-spiro[4,5]dec-8-yl)-2,2-dimethyl-propionitrileprepared above in step c (350 mg, 1.56 mmol, 1.0 equiv.) was dissolvedin trifluoroacetic acid (6.0 mL, 78 mmol, 50 equiv.) at 0° C. and theresulting reaction was treated with H₂O (280 μL, 15.6 mmol, 10 equiv.).After being stirred at 25° C. for 48 h, the reaction was concentratedunder reduced pressure. The reaction mixture was then basified (ice-cold1N aqueous NaOH) and extracted (5×10% MeOH/CH₂Cl₂). The combined organiclayer was dried (Na₂SO₄) and concentrated under reduced pressure toprovide the product as a yellow liquid.

e). A solution of 2,2-dimethyl-3-(4-oxo-piperidin-1-yl)-propanenitrileprepared above in step d (126 mg, 0.70 mmol, 1.0 equiv.),cyclopropylamine (97 μL, 1.40 mmol, 2.0 equiv.) and AcOH (80 μL, 1.40mmol, 2.0 equiv.) in 1,2-dichloroethane (3.6 mL) was treated at 0° C.with NaBH(OAc)₃ (296 mg, 1.40 mmol, 2.0 equiv.). After being stirred for16 h at 25° C., the reaction was diluted (CH₂Cl₂), basified (1 N aqueousNaOH and 1×brine) and extracted (5×10% MeOH/CH₂Cl₂). The combinedorganic layer were dried (Na₂SO₄) and concentrated under reducedpressure to provide the product as a yellow liquid.

f).(S)-N-[1-(2-cyano-2-methylpropyl)piperidin-4-yl]-N-cyclopropyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide.A solution of3-(4-(cyclopropylamino)piperidin-1-yl)-2,2-dimethylpropanenitrileprepared above in step e (152 mg, 0.69 mmol, 1.1 equiv.) and(S)-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoic acid (146 mg, 0.63mmol, 1.0 equiv.) in DMF (1.3 mL) was treated at 0° C. with EDCI (240mg, 1.25 mmol, 2.0 equiv.), HOAt (170 mg, 1.25 mmol, 2.0 equiv.) andNaHCO₃ (105 mg, 1.25 mmol, 2.0 equiv.) successively. After being stirredat 25° C. for 12 h, the reaction was diluted (EtOAc) and washed(1×saturated NaHCO₃, and 1×brine). The organic layer was dried (Na₂SO₄)and concentrated under reduced pressure. Purification of the residue byflash chromatography (SiO₂, 0-5% MeOH/CH₂Cl₂, gradient elution) gave thetitle compound as a white solid: ¹H NMR (CDCl₃, 400 MHz) δ 7.58 (d,J=8.3 Hz, 2H), 7.48 (d, J=8.5 Hz, 2H), 4.17-4.11 (m, 1H), 3.24-3.14 (m,2H), 2.58-2.50 (m, 6H), 2.17-2.04 (m, 2H), 1.90-1.84 (m, 2H), 1.79 (s,3H), 1.35 (s, 3H), 1.35 (s, 3H), 0.62-0.57 (m, 2H), 0.49-0.45 (m, 2H);MS(ESI) 438 [M+H]⁺.

Example 18 Preparation of(S)-N-{1-[(1-cyanocyclobutyl)methyl]piperidin-4-yl}-N-cyclopropyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide

Using steps a˜f described above in Example 17, but substituting1-cyano-cyclobutane-carboxylic acid ethyl ester forcyano-dimethyl-acetic acid ethyl ester in step (a), the title compoundwas prepared: ¹H NMR (DMSO, 500 MHz) δ 7.61 (d, J=8.1 Hz, 2H), 7.49 (d,J=8.0 Hz, 2H), 6.66 (s, 1H), 3.93-3.88 (m, 1H), 2.98-2.96 (m, 2H),2.76-2.72 (m, 1H), 2.66 (s, 2H), 2.38-2.35 (m, 2H), 2.19-2.14 (m, 4H),2.14-2.00 (m, 4H), 1.80-1.77 (m, 2H), 1.71 (s, 3H), 0.51-0.49 (m, 2H),0.37-0.33 (m, 2H); MS(ESI) 450 [M+H]⁺.

Example 19 Preparation of(S)-N-1-[(1-carbamoylcyclobutyl)methyl]piperidin-4-yl}-N-cyclopropyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide

Using the methods described in Example 4, but substituting(S)-N-{1-[(1-cyanocyclobutyl)methyl]piperidin-4-yl}-N-cyclopropyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamidefor(S)-N-[1-(4-cyanophenyl)piperidin-4-yl]-N-cyclopropyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide,the title compound was prepared: ¹H NMR (DMSO, 500 MHz) δ 7.66 (d, J=8.2Hz, 2H), 7.53 (d, J=8.2 Hz, 2H), 7.33 (br, s, 1H), 6.84 (br, s, 1H),6.72 (s, 1H), 3.95-3.91 (m, 1H), 2.95-2.93 (m, 2H), 2.77-2.71 (m, 1H),2.70 (s, 2H), 2.35-2.30 (m, 2H), 2.10-1.99 (m, 4H), 1.95-1.90 (m, 2H),1.85-1.77 (m, 4H), 1.77 (m, 3H), 0.55-0.54 (m, 2H), 0.41-0.37 (m, 2H);MS(ESI) 468 [M+H]⁺.

Example 20 Preparation of(S)-N-(1-{[1-(cyanomethyl)cyclobutyl]methyl}piperidin-4-yl)-N-cyclopropyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide

a). To a solution of [1-(hydroxymethyl)-cyclobutyl]methanol (2.50 g,21.5 mmol, 1.0 equiv.) which was prepared as described in the reference(F. X. Tavares et al., J. Med. Chem. 2004, 47, 5057-5068) in CH₂Cl₂ (43mL) was added SOCl₂ (2.35 mL, 32.3 mmol, 1.5 equiv.) slowly at 0° C.After being stirred for 2 h at 25° C., the reaction was diluted (10%MeOH/CH₂Cl₂) and washed (1×H₂O and 1×brine). The organic layer was dried(Na₂SO₄) and concentrated under reduced pressure to provide the productas a colorless liquid.

b). A solution of 6,8-dioxa-7-thia-spiro[3,5]nonane-7-oxide preparedabove in step (a) (1.28 g, 7.89 mmol, 1.0 equiv.) in DMF (8.0 mL) wastreated with Et₄NCN (2.47 g, 15.8 mmol, 2.0 equiv.). After being stirredat 70° C. for 12 h, the reaction was concentrated under reducedpressure. The reaction mixture was then diluted (10% MeOH/CH₂Cl₂) andwashed (1×H₂O and 1×brine). The organic layer was dried (Na₂SO₄) andconcentrated under reduced pressure to provide the product as a pale redliquid.

c). A solution of 2-[1-(hydroxymethyl)cyclobutyl]acetonitrile preparedabove in step (b) (463 mg, 3.70 mmol, 1.0 equiv.), Ph₃P (1.36 g, 5.18mmol, 1.4 equiv.), and imidazole (352 mg, 5.18 mmol, 1.4 equiv.) inCH₃CN/Et₂O (2/1, 18 mL) was treated at 0° C. with I₂ (2.63 g, 10.4 mmol,2.8 equiv.). After being stirred at 25° C. for 40 min, the reaction wasdiluted (EtOAc) and washed (1×1 M aqueous Na₂S₂O₃ and 1×brine). Theorganic layer was dried (Na₂SO₄) and concentrated under reducedpressure. Purification of the residue by flash chromatography (SiO₂,5-10% EtOAc/hexanes, gradient elution) gave the product as a yellowfilm.

d). A mixture of 2-[1-(iodomethyl)cyclobutyl]acetonitrile prepared abovein step (c) (342 mg, 1.45 mmol, 1.0 equiv.) and1,4-dioxa-8-azaspiro[4,5]decane (519 mg, 3.63 mmol, 2.5 equiv.) wasplaced in a sealed tube. After being stirred at 80° C. for 12 h, thereaction was diluted (EtOAc) and washed (1×1 N aqueous NaOH and1×brine). The organic layer was dried (Na₂SO₄) and concentrated underreduced pressure. Purification of the residue by flash chromatography(SiO₂, 0-5% MeOH/CH₂Cl₂, gradient elution) gave the product as acolorless liquid.

e).[1-(1,4-dioxa-8-aza-spiro[4,5]dec-8-ylmethyl)-cyclobutyl]-acetonitrileprepared above in step (d) (265 mg, 1.06 mmol, 1.0 equiv.) was dissolvedin trifluoroacetic acid (8.2 mL, 110 mmol, 100 equiv.) at 0° C. and theresulting reaction was treated with H₂O (380 μL, 21.2 mmol, 20 equiv.).After being stirred at 25° C. for 5 days, the reaction was concentratedunder reduced pressure. The reaction mixture was then basified (ice-cold1N aqueous NaOH) and extracted (5×10% MeOH/CH₂Cl₂). The combined organiclayer was dried (Na₂SO₄) and concentrated under reduced pressure toprovide the product as a yellow liquid.

f). A solution of2-{1-[(4-oxopiperidin-1-yl)methyl]cyclobutyl}acetonitrile prepared abovein step (f) (200 mg, 0.97 mmol, 1.0 equiv.), cyclopropylamine (134 μL,1.94 mmol, 2.0 equiv.) and AcOH (111 μL, 1.94 mmol, 2.0 equiv.) in1,2-dichloroethane (5.0 mL) was treated at 0° C. with NaBH(OAc)₃ (411mg, 1.94 mmol, 2.0 equiv.). After being stirred for 16 h at 25° C., thereaction was diluted (CH₂Cl₂), basified (1 N aqueous NaOH and 1×brine)and extracted (5×10% MeOH/CH₂Cl₂). The combined organic layer was dried(Na₂SO₄) and concentrated under reduced pressure to provide the productas a yellow liquid.

g).(S)-N-(1-{[1-(cyanomethyl)cyclobutyl]methyl}piperidin-4-yl)-N-cyclopropyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide.A solution of2-(1-{[4-(cyclopropylamino)piperidin-1-yl]methyl}cyclobutyl)acetonitrileprepared above in step (f) (247 mg, 0.97 mmol, 1.1 equiv.) and(S)-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoic acid (206 mg, 0.88mmol, 1.0 equiv.) in DMF (1.3 mL) was treated at 0° C. with EDCI (338mg, 1.76 mmol, 2.0 equiv.), HOAt (240 mg, 1.76 mmol, 2.0 equiv.) andNaHCO₃ (148 mg, 1.76 mmol, 2.0 equiv.) successively. After being stirredat 25° C. for 12 h, the reaction was diluted (EtOAc) and washed(1×saturated NaHCO₃, and 1×brine). The organic layer was dried (Na₂SO₄)and concentrated under reduced pressure. Purification of the residue byflash chromatography (SiO₂, 0-5% MeOH/CH₂Cl₂, gradient elution) gave thetitle compound as a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.60 (d,J=8.1 Hz, 2H), 7.49 (d, J=8.3 Hz, 2H), 4.86-4.84 (m, 1H), 2.88-2.84 (m,2H), 2.70-2.67 (m, 3H), 2.58-2.54 (m, 1H), 2.48 (s, 2H), 2.24-2.19 (m,2H), 2.14-1.89 (m, 8H), 1.88-1.78 (m, 2H), 1.81 (s, 3H), 0.62-0.57 (m,2H), 0.49-0.45 (m, 2H); MS(ESI) 464 [M+H]⁺.

Example 21 Preparation of(S)-N-(1-{1-(2-amino-2-oxoethyl)cyclobutyl]methyl}piperidin-4-yl)-N-cyclopropyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide

Using the methods described in Example 4, but substituting(S)-N-(1-{[1-(cyanomethyl)cyclobutyl]methyl}piperidin-4-yl)-N-cyclopropyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamidefor(S)-N-[1-(4-cyanophenyl)piperidin-4-yl]-N-cyclopropyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide,the title compound was prepared: ¹H NMR (CD₃OD, 500 MHz) δ 7.70 (d,J=8.1 Hz, 2H), 7.53 (d, J=8.3 Hz, 2H), 4.04-3.98 (m, 1H), 2.98-2.88 (m,2H), 2.80-2.70 (m, 1H), 2.62-2.48 (m, 4H), 2.27-2.10 (m, 4H), 2.07-1.80(m, 8H), 1.77 (s, 3H), 0.64-0.62 (m, 2H), 0.50-0.44 (m, 2H); MS(ESI) 482[M+H]⁺.

Example 22 Preparation of(S)-N-(1-{[1-(cyanomethyl)cyclopropyl]methyl}piperidin-4-yl)-N-cyclopropyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide

Using steps (a) through (g) described above in Example 20, butsubstituting [1-(hydroxymethyl)-cyclopropyl]methanol for[1-(hydroxymethyl)-cyclobutyl]methanol in step (a), the title compoundwas prepared: ¹H NMR (CD₃OD, 400 MHz) δ 7.58 (d, J=8.1 Hz, 2H), 7.48 (d,J=8.3 Hz, 2H), 4.19-4.14 (m, 1H), 3.11-3.05 (m, 2H), 2.58-2.50 (m, 4H),2.29 (s, 2H), 2.19-2.3 (m, 4H), 1.93-1.87 (m, 2H), 1.79 (s, 3H),0.63-0.56 (m, 4H), 0.49-0.45 (m, 4H); MS(ESI) 450 [M+H]⁺.

BIOLOGICAL EXAMPLES

Procedures Useful for the Biological Evaluation of the BenzamideDerivatives

In addition to the extensive literature disclosing the role of HSDs invarious diseases and disorders, described herein are assays useful fortesting the Benzamide Derivatives of the present invention.

Assays

In Vitro 11β-HSD1 (Hydroxysteroid Dehydrogenase 1) Activity InhibitoryAction

The 11β-HSD1 inhibitory activity was examined by quantitativedetermination by an SPA (scintillation proximity assay) system of thesuppressive action on the conversion from cortisone to cortisol usinghuman 11β-HSD1 (hereinafter recombinant 11β-HSD1) expressed using abaculo-virus system as an enzyme source. For the reaction, a reagent wasadded to a 96 well plate (96 well Opti-plates™-96 (Packard)) to thefollowing final concentration and a volume of 100 μl was reacted at roomtemperature for 90 min. The reaction solution used was 0.1 μg/mlrecombinant 11β-HSD1, 500 μM NADPH, 16 nM ³H cortisone (AmershamBiosciences, 1.78 Tbq/mol) dissolved in 0.1% BSA (Sigma)-containing PBSand the test drug was 2 μl of a compound solution (dissolved in DMSO).After 90 min, the reaction was stopped by adding PBS (40 μl, containing0.1% BSA (Sigma)) containing 0.08 μg of anti-cortisol mouse monoclonalantibody (East Coast Biologics), 365 μg SPA PVT mouse antibody-bindingbeads (Amersham Biosciences) and 175 μM carbenoxolone (Sigma) to thereaction solution. After the completion of the reaction, the plate wasincubated overnight at room temperature and the radioactivity wasmeasured by Topcount (Packard). For control, the value (0% inhibition)of the well containing 2 μl of DMSO instead of the test drug was used,and for positive control, the value (100% inhibition) of the wellcontaining carbenoxolone instead of the test drug at the finalconcentration of 50 μM was used. The inhibition (%) of the test drug wascalculated by ((value of control−value of test drug)/(value ofcontrol−value of positive control))×100(%). The IC₅₀ value was analyzedusing a computer-based curve fitting software.

This example provides assays that are useful in evaluating and selectinga compound that modulates 11β-HSD1.

Biochemical 11β-HSD1 Assay by SPA

Recombinant human, mouse and rat 11β-HSD1 were expressed in baculovirusexpression system, isolated by affinity purification and used as theenzyme sources for cortisone to cortisol conversion in vitro.³H-Cortisone (Amersham Bioscience, 1.78 Tbq/mol. 49 Ci/mmol) was used asthe substrate, and a monoclonal anti-cortisol antibody and thescintillation proximity assay (SPA) system were used to detect theproduct of the 11β-HSD1-catalyzed reaction, ³H-cortisol. Reactions tookplace at room temperature for 90 min. in 96-well Opti-plates™-96(Packard) in 100 μL volume with 2 μL test compounds or control in DMSO,0.1 μg/mL 11β-HSD1 protein, 500 μM NADPH and 16 nM radioactivecortisone, in PBS buffer supplemented with 0.1% BSA (Sigma). Reactionwas stopped with the addition of 40 μL buffer containing 0.08 μganti-cortisol monoclonal antibody (East Coast Biologics), 365 μg SPA PVTantibody-binding beads (Amersham Biosciences) and 175 μM carbenoxolone(Sigma).

Plates were incubated at room temperature overnight before being read ona Topcount (Packard). The point of 50% inhibition of 11β-HSD1 enzymeactivity (IC₅₀) was determined by computer-based curve fitting.

Cell-Based 11β-HSD1 Assay by SPA

This cell-based assay measures the conversion of ³H-cortisone to³H-cortisol in a HEK-293 cell line stably overexpressing humanrecombinant 11β-HSD1. HEK-293 cells were grown in DMEM/F12 supplementedwith 10% fetal bovine serum, and plated onto poly-D-lysine-coated96-well assay plates (Costar 3903), 100,000 cells per well in 50 μLassay media (phenol free DMEM/F12 (Invitrogen)+0.2% BSA+1%antibiotic-antimycotic solutions). The solution was incubated at 37° C.for 24 h, and the reaction was initiated by the addition of 25 μL ofassay media containing compounds of desired concentration and 25 μL ofassay media containing 40 nM of ³H-cortisone to each well. The reactionmixture was incubated at 37° C. for 90 min. and the reaction terminatedby the addition of 25 μL of assay media containing 0.2 μg ofanti-cortisol monoclonal antibody (East Coast Biologics), 500 μg SPA PVTantibody-binding beads (Amersham Biosciences) and 500 μM carbenoxolone(Sigma).

Plates were incubated at room temperature for at least 2 h before beingread on Topcount (Packard). The point of 50% inhibition of 11β-HSD1enzyme activity (IC₅₀) was determined by computer-based curve fitting.

Scintillation Proximity Assay

[1,2(n)-³H]-cortisone was purchased from Amersham Pharmacia Biotech.Anti-cortisol monoclonal mouse antibody, clone 6D6.7 was obtained fromImmunotech and Scintillation proximity assay (SPA) beads coated withmonoclonal antimouse antibodies were from Amersham Pharmacia Biotech.NADPH, tetrasodium salt was from Calbiochem and glucose-6-phosphate(G-6-P) was supplied by Sigma. The human 11-β-hydroxysteroiddehydrogenase type-1 enzyme (11-β-HSD₁) was expressed in Pichiapastoris. 18-β-glycyrrhetinic acid (GA) was obtained from Sigma. Theserial dilutions of the compounds were performed on a Tecan Genesis RSP150. Compounds to be tested were dissolved in DMSO (1 mM) and diluted in50 mM Tris-HCl, pH 7.2 containing 1 mM EDTA.

The multiplication of plates was done on a WallacQuadra. The amount ofthe product [³H]-cortisol, bound to the beads was determined in aPackard, Top Count microplate liquid scintillation counter.

The 11-β-HSD₁ enzyme assay was carried out in 96 well microtiter plates(Packard, Optiplate) in a total well volume of 220 μL and contained 30mM Tris-HCl, pH 7.2 with 1 mM EDTA, a substrate mixture tritiatedCortisone/NADPH (175 nM/181 μM), G-6-P (1 mM) and inhibitors in serialdilutions (9 to 0.15 μM). Reactions were initiated by the addition ofhuman 11-β-HSD₁, either as Pichia pastoris cell homogenate or microsomesprepared from Pichia pastoris (the final amount of enzyme used wasvaried between 0.057 to 0.11 mg/mL). Following mixing, the plates wereshaken for 30 to 45 minutes at room temperature. The reactions wereterminated with 10 μL 1 mM GA stop solution. Monoclonal mouse antibodywas then added (10 μL of 4 μM) followed by 100 μL of SPA beads(suspended according to the manufacturers instructions). Appropriatecontrols were set up by omitting the 11-β-HSD₁ to obtain thenon-specific binding (NSB) value.

The plates were covered with plastic film and incubated on a shaker for30 minutes, at room temperature, before counting. The amount of[³H]-cortisol, bound to the beads was determined in a microplate liquidscintillation counter. The calculation of the K_(i) values for theinhibitors was performed by use of Activity Base. The K_(i) value iscalculated from IC₅₀ and the K_(m) value is calculated using the ChengPrushoff equation (with reversible inhibition that follows theMichaelis-Menten equation): K_(i)=IC₅₀(1+[S]/K_(m)) [Cheng, Y. C.;Prushoff, W. H. Biochem. Pharmacol. 1973, 22, 3099-3108]. The IC₅₀ ismeasured experimentally in an assay wherein the decrease of the turnoverof cortisone to cortisol is dependent on the inhibition potential ofeach substance.

Cloning, Expression and Purification of 11β-HSD1

The expression and purification of the murine enzyme is described by J.Zhang, et al. Biochemistry, 44, 2005, pp 6948-57. The expression andpurification of the human enzyme is similar to that of the murinesequence.

Enzyme Assay:

The IC50 and Ki of the compounds are determined by the following method:

1. Prepare an Assay Buffer, (pH 7.2, 50 mM Tris-HCL, 1 mM EDTA) fresheach week.

2. Prepare the following solutions:

NADPH (Sigma, 200 μM)

³H-Cortisone(Amersham Biosciences, 45 Ci/mmol, 200 nM)

Enzyme Prep (20 nM for human, 10 nM for mouse)

Cortisol Antibody (East Coast Biologicals, (1:50 dilution)

Anti-mouse SPA beads (Amersham Biosciences, 15 mg/ml)

18β-Glycyrrhetinic acid (“GA”)(Aldrich, 1 μM)

Compound Stock Solution(10 mM in DMSO), serially diluted in assaybuffer. Each compound is tested at six different concentrations usually(10 μM to 0.1 nM). All of the solutions and dilutions are made in theAssay Buffer.

3. Assay is run using white/white, 96-well assay plates (Corning) in atotal volume of 100 μL.

4. Into each well of a 96-well plate is added Assay Buffer (30 μL),compound (10 μL) NADPH (10 μL), and ³H-cortisone (10 μL).

5. Initiate reaction by adding 40 μL of HSD-1 enzyme prep to the wells.

6. The plate is covered with tape and incubated on an orbital shaker for1 h at RT.

7. After 1 h, the tape is removed and anti-cortisol antibody (10 μL), GAsolution (10 μL), and SPA bead preparation (100 μL) is added.

8. The plate is incubated (30 min) on an orbital shaker at RT.

9. The counts are read on a TopCount NXT reader.

10. A dose-response curve is first plotted using the Graphpad Prismsoftware, to generate the IC50 values.

With this IC50 value and the known Km value for the substrate and HSD1enzyme, an estimated Ki can be calculated with the Chen and Prusoffequation {Ki=IC50/[1+(substrate/Km)]}.

The compounds of the present invention all show 11β-HSD1 enzyme activity(IC₅₀) in the assays ranging from 1000 nM to <1 nM.

1. A compound having the formula (I):

or pharmaceutically acceptable salts, solvates, stereoisomers orprodrugs thereof, wherein: R¹ is a member selected from the groupconsisting of —OH, halogen and (C₁-C₈)haloalkyl; R² and R³ are membersindependently selected from the group consisting of halogen,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy,(C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl and (C₃-C₈)cycloalkyl, wherein nomore than two of R¹, R² and R³ are halogen; R⁴ is a member selected fromthe group consisting of hydrogen, halogen, (C₁-C₈)alkyl and(C₃-C₈)cycloalkyl; R⁵ is selected from the group consisting of(C₁-C₈)alkyl, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl, (C₃-C₈)cycloalkyl,and (C₃-C₈)heterocycloalkyl, wherein any cycloalkyl or heterocycloalkylportion is optionally substituted with from one to two members selectedfrom the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl,(C₂-C₄)hydroxyalkyl, and (C₁-C₄)alkoxy; X is selected from the groupconsisting of a bond, (C₁-C₈)alkylene, (C₀-C₈)alkylene-SO₂, and(C₀-C₈)alkylene-C(O); Y is selected from the group consisting of H, —CN,—N(R′)₂, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)haloalkyl,(C₂-C₈)hydroxyalkyl, (C₃-C₈)cycloalkyl, (C₃-C₈)heterocycloalkyl,heteroaryl, and aryl, wherein any cycloalkyl portion, heterocycloalkylportion, aryl portion or heteroaryl portion is optionally substitutedwith from one to four members selected from the group consisting ofhalogen, —CN, —NO₂, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₁-C₈)alkoxy, ═O, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl, aryl,heteroaryl, (C₃-C₈)cycloalkyl, (C₃-C₈)heterocycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, (C₃-C₈)heterocycloalkyl(C₁-C₆)alkyl,heteroaryl(C₁-C₆)alkyl or aryl(C₁-C₆)alkyl, —C(O)R′, —C(O)OR′,—NR′C(O)OR′, —OR′, —SR′, —OC(O)R′, —C(O)N(R′)₂, —S(O)R′, —SO₂R′,—SO₂N(R′)₂, —N(R′)₂, —NR′C(O)R′, —NR′SO₂R′, -Z-C(O)R′, -Z-CN,-Z-C(O)OR′, -Z-NR′C(O)OR′, -Z-OR′, -Z-OC(O)R′, -Z-C(O)N(R′)₂, -Z-S(O)R′,-Z-SO₂R′, -Z-SO₂N(R′)₂, -Z-N(R′)₂ and -Z-NR′C(O)R′; R⁶ to R⁹ are membersindependently selected from hydrogen and (C₁-C₈)alkyl; Z is a branchedor straight chain (C₁-C₈)alkylene group; each occurrence of R′ isindependently H or an unsubstituted member selected from the groupconsisting of (C₁-C₈)alkyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl, (C₁-C₈)haloalkyl,(C₂-C₈)hydroxyalkyl, or two R′ groups, when attached to the samenitrogen atom, can be combined with the nitrogen atom to which they areattached to form a heterocycle or heteroaryl group.
 2. The compound ofclaim 1, wherein R¹ is —OH, R² is (C₁-C₃)alkyl, R³ is (C₁-C₃)haloalkyl,and R⁵ is selected from (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, and(C₃-C₆)cycloalkyl.
 3. The compound of claim 2, wherein R⁵ iscyclopropyl.
 4. The compound of claim 1, wherein R¹ is —OH, R² ismethyl, and R³ is trifluoromethyl.
 5. The compound according to claim 4,wherein R¹, R², and R³, together with the carbon atom to which they areattached, are an (S)-trifluoromethyl carbinol group of the formula:


6. The compound according to claim 4, wherein R¹, R², and R³, togetherwith the carbon atom to which they are attached, are an(R)-trifluoromethyl carbinol group of the formula:


7. A pharmaceutical composition comprising the compound of claim 1, anda pharmaceutically acceptable carrier.
 8. A pharmaceutical compositioncomprising the compound of claim 1, and an additional therapeutic agent.9. A method of treating a disease or condition selected from the groupconsisting of diabetes, obesity, dyslipidemia, hyperinsulinemia,glaucoma, osteoporosis, cognitive disorders, atherosclerosis, immunedisorders, hypertension and wound healing in a patient in need thereofcomprising administering to the patient a therapeutically effectiveamount of the compound of claim
 1. 10. The method according to claim 9,wherein the disease or condition is diabetes, obesity, hyperlipidemia,hypercholesterolemia, hypertriglyceridemia, low level of high-densitylipoprotein, hyperinsulinemia, or atherosclerosis.
 11. The method ofclaim 10, wherein the condition or disorder is diabetes or obesity. 12.A method of treating a condition or disorder responsive to themodulation of a hydroxysteroid dehydrogenase, comprising administeringto a patient in need thereof a therapeutically effective amount of acompound of claim
 1. 13. The method of claim 12, wherein saidhydroxysteroid dehydrogenase is selected from the group consisting of11β-HSD1, 11β-HSD2 and 17β-HSD3.
 14. A compound selected from the groupconsisting of:

or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrugthereof.